Block copolymers of cyclic esters and processes for preparing same

ABSTRACT

Novel processes of preparing block polyester copolymers while precisely controlling the stereoconfiguration (e.g., tacticity), chemical composition and/or length of each unit (block) are provided. Block polyester copolymers featuring desirable combinations of two or more blocks featuring different stereoconfiguration (e.g., tacticity), chemical composition and/or length, including triblock, tetrablock and higher block copolymers are also provided. A novel family of organometallic magnesium complexes and uses thereof in preparing polyesters and block polyester copolymers are also provided.

RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No.15/756,131 filed on Feb. 28, 2018, which is a National Phase of PCTPatent Application No. PCT/IL2017/050735 having International FilingDate of Jun. 29, 2017, which claims the benefit of priority under 35 USC§ 119(e) of U.S. Provisional Patent Application No. 62/356,038 filed onJun. 29, 2016. The contents of the above applications are allincorporated by reference as if fully set forth herein in theirentirety.

FIELD AND BACKGROUND OF THE INVENTION

The present invention, in some embodiments thereof, relates to chemistryand, more particularly, but not exclusively, to block polyestercopolymers, including, but not limited to, stereoblock polyestercopolymers, featuring high precision, and to one-pot ring openingpolymerization processes for preparing same.

Block copolymers are copolymers consisting of regularly or statisticallyalternating two or more different homopolymer blocks that differ incomposition or structure. Each homopolymer block in a block copolymerrepresents polymerized monomers of one type. The homopolymer blocks candiffer from one another by the chemical composition of the monomerscomposing each homopolymer block and/or by the stereoconfiguration ofthe homopolymer block (e.g. isotactic and syndiotactic configurations).

For example, while copolymers composed of A and B monomers may bearranged is a random or alternating fashion as follows:-A-A-B-A-B-B-A-B-A-A-B-B-B-A-  random copolymer-A-B-A-B-A-B-A-B-A-B-A-B-A-B-  alternating capolymer

Block copolymers comprise clusters of monomers A and B as exemplified inthe following non-limiting example of a diblock copolymer:-A-A-A-A-A-A-A-B-B-B-B-B-B-B-  block copolymer

Block copolymers typically combine the properties of their constituentblocks, thus differentiating such copolymers from random copolymers thatdo not exhibit the characteristics of each of their components.

The number of homopolymer blocks may be specific (e.g., diblock,triblock, tetrablock, etc.) or non-specific, if the blocks are formedrandomly (multiblock).

The properties of block copolymers may be similar to the sum of theproperties of a mixture of the homopolymers composing them, but thepresence of chemical bonds between the blocks ensures their stabilityand prevents their separation with the release of individual components.In addition, block copolymers may exhibit unique properties such asformation of micelles. Synthesis of block copolymers significantlyexpands the possibilities for modifying the properties of polymers. Thecombination of properties of homopolymers in a block copolymer typicallymanifests itself in the thermomechanical properties and transitiontemperatures of block copolymers.

Among the sophisticated polymers, block copolymers are the mostimportant group, because they can lead to materials that combinedesirable properties of each of the blocks, such as, for example,crystallinity and elasticity, and to specialty morphologies such aslamellae, rods or spheres by microphase separation of the blocks intospecific regimes.

Plastic materials play an inseparable role of modern life. Their readyavailability from cheap starting materials combined with establishedtechnologies for their production, and their immense range of propertiesmake them core ingredients in durable goods such as constructionmaterials, household items, fibers, and auto parts, in disposablematerials such as food packaging disposable cups and plates, and inbiomedical and biocompatible products including artificial implants,stents, sutures, etc.

The properties of plastic materials are derived from their molecularstructure, namely, the building blocks from which the polymer chains arebuilt, the type and degree of regularity of the building blocks in thechains, such as the regioregularity and stereoregularity, the generaltype of the polymer, e.g., linear, branched, or cross-linked typepolymer, and the possibility of combining different building blockseither within the same chain or in mixtures of separate chains.Properties such as melting transition, glass transition, impactresistance, tackiness, film formation, gas permeability, rate ofdecomposition, etc., are a direct outcome of the specific structure ofthe polymeric material.

The ability to manufacture polymeric materials having a ‘tailor-made’structure is a key-step on the way to improving the properties ofexisting plastics, replacing old plastics with new ones having lowerenvironmental signature, and finding new applications for plasticmaterials.

Biodegradable plastic materials derived from bio-renewable resourcessuch as poly(lactic acid) (PLA) are attracting considerable currentinterest. PLA combines promising mechanical and physical properties andis produced from starting materials originating from biomass such ascorn. As the degradation products of PLA are non-toxic, it has foundbiomedical applications (sutures, implants, pulmonary stents, scaffoldsfor tissue engineering, etc.) as well as commodity applications.

The most practical method for the production of PLA and relatedpolyesters is the catalytic Ring Opening Polymerization (ROP) of cyclicesters (lactones).

Lactide is chiral having two stereogenic centers leading to threepossible stereoisomers: L-lactide (the natural stereoisomer), D-lactide,and meso-lactide.

Ring opening polymerization of lactides may therefore lead to PLAs ofvarious tacticities, as shown in Background Art FIG. 1 .

The properties of PLA are determined by its microstructural regularity.Isotactic PLA, composed of identical repeat units of either L-LA or D-LAis a crystalline polymer. PDLA and PLLA, the two enantiomeric homochiralstrands, co-crystallize as a stereocomplex (SC) phase whose propertiesare superior to those of the homochiral (HC) crystal phase. However,this crystallization tendency diminishes for higher molecular weightPLA.

More advanced PLA generations are expected to include different types oflactide isomers assembled in an ordered (regioregular) fashion, and inparticular block copolymers. In particular, isotactic stereoblock-PLAcomposed of covalently bound PDLA and PLLA blocks has been targeted.

Copolymers of PLA and related aliphatic polyesters have also been foundhighly useful in biomedicine and pharmaceutics. In particular,copolymers of PLA and poly(F-caprolactone) (PCL) have been explored ascomponents of drug delivery systems, dissolvable sutures and scaffoldsfor tissue engineering. The two polymers are immiscible, thus exhibitingdistinct melting and crystallization temperatures when mixed. However,when copolymerized, an improved polymer is obtained having versatilethermal and mechanical properties and adjustable degradation time. Whilegradient multiblock or random copolymers of PLA and PCL are usuallyamorphous, block copolymers of PLA and PCL are crystalline materials.Stereocomplexation was observed in blends of enantiomeric PLA-PCLdiblock and symmetric triblocks copolymers, exhibiting higher meltingtemperatures compared to enantiomeric copolymers. Therefore, copolymersof PCL with PLA stereoblocks have also been targeted.

Tailor-made plastics such as described hereinabove require sophisticatedcatalysts, and, in the past 15 years, there has been an enormous effortto try and develop more advanced catalysts.

The most successful catalysts for lactide and related cyclic-esterpolymerizations are metal complexes featuring a chelating ligand thatremains bound to the metal, and a labile alkoxo group that initiates thepolymerization process. Some of the catalysts described in theliterature in the past years, were reported to be living, and werereported to lead to diblock and triblock copolymers of lactideenantiomers, or lactide and related cyclic esters. See, for example,Othman et al. Polymer 53, 2443 (2012); Aluthge et al. Macromolecules 46,3965 (2013); and Amgoune et al. Chem. Eur. J. 2006, 12, 169.

However, these catalysts suffer from high cost of the metal, andrelative sluggishness (for the indium). For example, Othman et al.(2012) report on the synthesis of isotactic stereo-diblock PLA of someprecision employing a living catalyst, in which two “overnight” periodswere required for full monomer consumption.

Additional Background art includes Wheaton et al. Dalton Trans. 2009,4832-4846; Chisholm et al. J. Am. Chem. Soc. 2000, 122, 11845-11854;Chamberlain et al. J. Am. Chem. Soc. 2001, 123, 3229-3238; Chen et al.Macromolecules 2006, 39, 3745-3752; Darensbourg et al. Inorg. Chem.2010, 49, 2360-2371; and Yu et al. Organometallics, 2013, 32, 3262-3268,which teach catalysts for lactide ring opening polymerization in whichzinc is embedded in various ligand environments. While a few of thesecatalysts exhibit high activities, they traditionally tend to be eithernon-stereoselective or heteroselective.

Isoselective polymerization of rac-LA has been reported, for example, byWang and Ma, Chem. Commun. 2013, 49, 8686-8688; Wang et al.Macromolecules 2014, 47, 7750-7764; Abbina and Du, ACS Macro. Lett.2014, 3, 689-692; Mou et al. Chem. Commun. 2014, 50, 11411-11414;Honrado et al. Organometallics, 2015, 34, 3196-3208.

A zinc catalyst obtainable using a pre-catalyst featuring an ethylzincbound to a tridentate monoanionic diamine-monophenolate {ONN} ligand,the structure of which is presented below, was shown to exhibit veryhigh activity in lactide ROP, upon addition of ethyl alcohol, consuming500 equivalents of rac-LA in 5 minute at room temperature [Williams etal. J. Am. Chem. Soc. 2003, 125, 11350-11359]. However, the PLA obtainedusing this catalyst was atactic. This catalyst was found to be dinuclearin the solid state and mononuclear in solution.

-   -   tridentate {ONN}-H ligand precursor.

A later attempt to induce stereoselectivity by employing a chiraldiaminocyclohexane-based ligand led to a robust zinc complex, whoseethyl group could not be readily replaced with an active alkoxo group[Labourdette et al. Organometallics, 2009, 28, 1309-1319].

Recently, a tetradentate monoanionic ligand featuring a chiralbipyrrolidine core and phenolate and pyridine peripheral donors wasdescribed in the context of iron electrochemistry [Chiang et al. Inorg.Chem. 2014, 53, 5810-5819].

Additional background art includes Rosen et al. Chem. Eur. J. 2016, 22,11533-11536; Fliedel et al. Dalton Trans. 44, 12376 (2015); Ajellal etal. Dalton Trans. 39, 8363 (2010); Carpentier, J.-F., & Sarazin, Y. Top.Organomet. Chem. 45, 141 (2013); Tschan et al., Dalton Trans., 2014, 43,4550; Rosen et al., J. Am. Chem. Soc. 2016, 138, 12041-12044; and Rosenet al., DOI: 10.1039/c7sc01514c.

SUMMARY OF THE INVENTION

Block copolymers are expected to play important roles in futureapplications such as biomedical applications, particularly blockpolyester copolymers.

The present inventors have now designed and successfully practiced amethodology for obtaining block copolymers including diblocks,triblocks, and the unprecedented tetrablocks and hexablocks and higherblock polyester copolymers. The designed methodology employs a recentlydisclosed group of Mg/Zn/Ca-based organometallic complexes featuringsequential or divergent {ONNN} ligand, along with a hydroxy-containinginitiator, and is effected by the sequential addition of different typesof cyclic ester monomers which differ from one another bystereoconfiguration and/or chemical composition, such as, for example,different diastereoisomers of lactide, optionally in combination with alactone (e.g., F-caprolactone). These catalyst systems exhibit anexceptional combination of high activity and well-behaved characterleading to active and living catalysts.

The production of novel tailor-made polymeric materials with possiblebiomedical and other applications is described. Some embodiments of thepresent invention relate to processes of preparing block copolymers ofcyclic esters, in particular stereoblock copolymers of chiral cyclicesters such as lactides, and block copolymers of lactones and lactides,and to block polyester copolymers featuring precise controllability oftheir structural features and properties.

Some embodiments of the present invention relate to novel magnesiumcomplexes featuring divergent {ONNN} ligands, to novel ligand precursorsusable in preparing such complexes and to processes of preparingpolymers of cyclic esters and block copolymers of cyclic esters,including stereoblocks of chiral cyclic esters, utilizing thesecomplexes.

According to an aspect of some embodiments of the present inventionthere is provided a process of preparing a block copolymer comprising aplurality of units, at least two of the units independently comprise aplurality of polymerized monomers of a cyclic ester, at least one unitof the at least two units comprises a plurality of polymerized monomersof a first cyclic ester, and at least one another unit of the at leasttwo units comprises a plurality of polymerized monomers of a secondcyclic ester, the second cyclic ester differing from the first cyclicester by a stereoconfiguration and/or a chemical composition, theprocess comprising:

sequentially contacting a plurality of monomers of the first cyclicester and a plurality of monomers of the second cyclic ester with acatalyst system comprising an initiator and a {ONNN}M-X complex, whereinM is a divalent metal and X is a monoanionic ligand, to therebysequentially effect a ring opening polymerization of the first cyclicester and of the second cyclic ester.

According to some of any of the embodiments described herein, the blockcopolymer further comprises at least one additional unit comprising aplurality of polymerized monomers of a third cyclic ester, the thirdcyclic ester differing from each of the first cyclic ester and thesecond cyclic ester by a stereoconfiguration and/or a chemicalcomposition, the process comprising:

sequentially contacting a plurality of monomers of the first cyclicester, a plurality of monomers of the second cyclic ester, and aplurality of monomers of the third cyclic ester, at any order, with acatalyst system comprising an initiator and a {ONNN}M-X complex, whereinM is a divalent metal and X is a monoanionic ligand, to therebysequentially effect a ring opening polymerization of the first cyclicester, of the second cyclic ester and of the third cyclic ester, ay anyof the order.

According to some of any of the embodiments described herein, at leastone pair of adjacent units comprises one unit comprising a plurality ofpolymerized monomers of the first cyclic ester, and one unit comprisinga plurality of polymerized monomers of the second cyclic ester, suchthat the block copolymer comprises at least two adjacent units differingfrom one another by a stereoconfiguration and/or a chemical composition.

According to some of any of the embodiments described herein, the blockcopolymer comprises from 2 to 10 units.

According to some of any of the embodiments described herein, at leasttwo units in the plurality of units differ from one another by a numberof the polymerized monomers.

According to some of any of the embodiments described herein, the atleast two units which differ from one another by a number of polymerizedmonomers form a pair of adjacent units in the block copolymer.

According to some of any of the embodiments described herein, at least90%, or at least 95% or at least 96% or at least 98% or at least 99% ofpolymerized monomers in each of the units feature the samestereoconfiguration and/or chemical composition.

According to some of any of the embodiments described herein, the blockcopolymer is a diblock copolymer, and wherein the diblock copolymer isobtained within less than 2 hours, or less than one hour.

According to some of any of the embodiments described herein, thering-opening polymerization is a living polymerization or an immortalpolymerization.

According to some of any of the embodiments described herein, thesequential contacting comprises contacting a plurality of monomers ofthe first cyclic ester with the catalyst system for a first time period;and, subsequent to the first time period, contacting a plurality ofmonomers of second cyclic ester for a second time period, and,optionally, subsequent to the second time period, contacting anadditional plurality of monomers, being either of the first cyclic esteror of a third cyclic ester which differs from the first and secondcyclic esters by a stereoconfiguration and/or chemical composition, fora third time period; and, further optionally, subsequent to the thirdtime period, contacting a plurality of monomers of a second cyclic esteror of a cyclic ester different from the third cyclic ester or the firstcyclic ester, for a fourth time period, and, further optionally,sequentially contacting a plurality of monomers of different cyclicesters, for additional time periods, according to a desirable number ofunits in the block copolymer and a desirable number of different blocksin the block copolymer.

According to some of any of the embodiments described herein, each ofthe first, second, and optionally third, fourth and additional, timeperiods independently ranges from 1 minute to 6 hours, or from 1 minuteto 3 hours, or from 1 minute to 2 hours, or from 1 minute to one hour,or from 1 minute to 30 minutes, or from 5 minutes to 30 minutes or from5 minutes to 20 minutes.

According to some of any of the embodiments described herein, the blockcopolymer is a stereoblock copolymer comprising at least one unit ofpolymerized monomers of the first cyclic ester and at least one unit ofpolymerized monomers of a second cyclic ester, the first cyclic esterfeaturing a first stereoconfiguration and the second cyclic esterfeaturing a second stereoconfiguration, the first and the secondstereoconfigurations being different from one another.

According to some of any of the embodiments described herein, theprocess comprises sequentially contacting a plurality of monomers of thefirst cyclic ester featuring the first stereoconfiguration and aplurality of monomers of the second cyclic ester featuring the secondstereoconfiguration with the catalyst system.

According to some of any of the embodiments described herein, at least90%, or at least 95% or at least 96% or at least 98% or at least 99% ofthe polymerized monomers in each of the units feature the samestereoconfiguration.

According to some of any of the embodiments described herein, a chemicalcomposition of the first cyclic ester and the second cyclic ester is thesame.

According to some of any of the embodiments described herein, at leastone of the first and second cyclic esters is a lactide.

According to some of any of the embodiments described herein, thelactide is selected from a homochiral lactide, a racemic lactide and ameso lactide.

According to some of any of the embodiments described herein, at leastone of the first and second cyclic esters is a lactone, for example, acaprolactone such as 8-caprolactone.

According to an aspect of some embodiments of the present inventionthere is provided a process of preparing a block copolymer comprising aplurality of units, at least two adjacent units in the plurality ofunits independently comprise a plurality of polymerized monomers of acyclic ester, at least one unit of the at least two adjacent unitscomprises a plurality of polymerized monomers of a first cyclic ester,and at least one another unit of the at least two adjacent unitscomprises a plurality of polymerized monomers of a second cyclic ester,the second cyclic ester differing from the first cyclic ester by astereoconfiguration and/or a chemical composition, the processcomprising sequentially subjecting a plurality of monomers of the firstcyclic ester and the second cyclic ester to a condition for effectingring-opening polymerization of the cyclic esters.

According to some of any of the embodiments described herein, thecondition for effecting the ring opening polymerization comprisescontacting the plurality of monomers of the cyclic ester with a catalystsystem that promotes the ring opening polymerization.

According to some of any of the embodiments described herein, thecatalyst system comprises an initiator and a {ONNN}M-X complex, whereinM is a divalent metal and X is a monoanionic ligand.

According to some of any of the embodiments described herein, theinitiator comprises at least one hydroxy group.

According to some of any of the embodiments described herein, theinitiator comprises a plurality of hydroxy groups.

According to some of any of the embodiments described herein, a molratio of the organometallic complex and the initiator ranges from 1:1 to1:1000.

According to some of any of the embodiments described herein, thesequential contacting is at room temperature.

According to some of any of the embodiments described herein, thesequential contacting is in a solution.

According to some of any of the embodiments described herein, theprocess is a one-pot process.

According to some of any of the embodiments described herein, theorganometallic complex is represented by Formula I:

wherein:

the dashed line represents a coordinative bond;

M is the divalent metal;

X is the monoanionic ligand as described herein in any of the respectiveembodiments;

A, B_(A) and B_(B) are each independently a bridging moiety of 1 to 12carbon atoms;

R₁ and R₂ are each independently hydrogen, alkyl, cycloalkyl, aryl oralternatively, one or both of R₁ and R₂ form together, optionally withone or more carbon atoms in A, a heteroalicyclic or heteroaromatic, 5 to7-membered ring; and

R₃ and R₄ are each independently hydrogen, alkyl, cycloalkyl, aryl oralternatively, one or both of R₃ and R₄ form together with one or morecarbon atoms in B₂, a heteroalicyclic or heteroaromatic, 5 to 7-memberedring.

According to some of any of the embodiments described herein, M ismagnesium.

According to some of any of the embodiments described herein, at leastone, or each, of the cyclic esters is a lactide, and wherein X is halo.

According to some of any of the embodiments described herein, at leastone of the first and second cyclic ester is a lactone and wherein X is asubstituted amine.

According to some of any of the embodiments described herein, thecomplex is represented by Formula IA:

wherein:

R₂₃-R₃₀ are each independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl, aryl, halo, alkoxy, aryloxy, trialkylsilyl,heteroalicyclic, heteroaryl, and amine.

According to an aspect of some embodiments of the present inventionthere is provided a block copolymer of a cyclic ester obtainable by theprocess as described herein in any of the respective embodiments and anycombination thereof.

According to an aspect of some embodiments of the present inventionthere is provided a block copolymer of a cyclic ester comprising aplurality of units, at least two of the units independently comprise aplurality of polymerized monomers of a cyclic ester, wherein one of theat least two units comprises a plurality of polymerized monomers of afirst cyclic ester and a another one of the at least two units comprisesa plurality of polymerized monomers of a second cyclic ester, the firstcyclic ester and the second cyclic ester differ from one another by achemical composition and/or a stereoconfiguration, wherein:

at least 90%, or at least 95% or at least 96% or at least 98% or atleast 99% of the polymerized monomers in each of the at least two unitsare identical to one another; and/or

a number of polymerized monomers in at least two of the plurality ofunits is different; and/or

the block copolymer comprises at least 3, or at least 4 units ofpolymerized monomers of the cyclic ester.

According to some of any of the embodiments described herein, the atleast two units independently comprising a plurality of polymerizedmonomers of the first cyclic ester and of the second cyclic ester areadjacent units.

According to some of any of the embodiments described herein, the cyclicester comprises at least one stereocenter and wherein at least two ofthe units differ from one another by a stereoconfiguration of the cyclicester.

According to some of any of the embodiments described herein, the cyclicester is lactide.

According to some of any of the embodiments described herein, each ofthe units comprises polymerized monomers featuring a polymericconfiguration selected from a linear polymeric chain and branchedpolymeric chains.

According to some of any of the embodiments described herein, the blockcopolymer characterized by a polydispersity (Mw/Mn) lower than 1.5, orlower than 1.2.

According to some of any of the embodiments described herein, the blockcopolymer is characterized by a Tm of at least 200° C.

According to some of any of the embodiments described herein, the blockcopolymer is characterized by a substantial heat of melting of at least40 J/g, or 50 J/g, or 60 J/g, or 70 J/g, or 80 J/g.

According to an aspect of some embodiments of the present inventionthere is provided a process of ring opening polymerization of a cyclicester, the process comprising contacting a plurality of monomers of thecyclic ester with a catalyst system comprising an organometallicmagnesium complex, the organometallic magnesium complex comprising aMg—X unit and a divergent {ONNN} ligand in coordination with the Mg—X.

According to some of any of the embodiments described herein, themagnesium complex is represented by Formula IIA or IIB, as describedherein in any of the respective embodiments.

According to some of any of the embodiments described herein, thecomplex is represented by Formula III, as described herein in any of therespective embodiments.

According to some of any of the embodiments described herein, thepolymer is a block copolymer comprising a plurality of units, at leasttwo of the units independently comprise a plurality of polymerizedmonomers of a cyclic ester, at least one unit of the at least two unitscomprises a plurality of polymerized monomers of a first cyclic ester,and at least one another unit of the at least two units comprises aplurality of polymerized monomers of a second cyclic ester, the secondcyclic ester differing from the first cyclic ester by astereoconfiguration and/or a chemical composition, the processcomprising:

sequentially contacting a plurality of monomers of the first cyclicester and a plurality of monomers of the second cyclic ester with thecatalyst system comprising an initiator and an organometallic magnesiumcomplex comprising a Mg—X unit and a divergent {ONNN} ligand incoordination with the Mg—X, to thereby sequentially effect a ringopening polymerization of the first cyclic ester and of the secondcyclic ester.

According to an aspect of some embodiments of the present inventionthere is provided an organometallic complex represented by Formula IIIor by Formula IIB, as described herein in any of the respectiveembodiments.

According to an aspect of some embodiments of the present inventionthere is provided a ligand precursor represented by Formula IV, asdescribed herein in any of the respective embodiments.

Further according to embodiments of the present invention there areprovided processes, block polyester copolymers, and catalyst systemsessentially as described herein.

Unless otherwise defined, all technical and/or scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which the invention pertains. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of embodiments of the invention, exemplarymethods and/or materials are described below. In case of conflict, thepatent specification, including definitions, will control. In addition,the materials, methods, and examples are illustrative only and are notintended to be necessarily limiting.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

Some embodiments of the invention are herein described, by way ofexample only, with reference to the accompanying drawings. With specificreference now to the drawings in detail, it is stressed that theparticulars shown are by way of example and for purposes of illustrativediscussion of embodiments of the invention. In this regard, thedescription taken with the drawings makes apparent to those skilled inthe art how embodiments of the invention may be practiced.

In the drawings:

FIG. 1 (Background Art) presents a schematic illustration of ringopening polymerization of lactides and the PLAs featuring varioustacticities afforded thereby;

FIG. 2 presents the crystallographic structure of an exemplary{ONNN}Mg—Cl complex according to some embodiments of the presentinvention;

FIG. 3 presents the crystallographic structure of an exemplary{ONNN}Mg-HMDS complex according to some embodiments of the presentinvention;

FIG. 4 is a schematic illustration of a one-pot synthesis of poly(lacticacid) homopolymers and isotactic stereoblock copolymers;

FIGS. 5A-5C present homodecoupled ¹H NMR spectra of PLA samples, withFIG. 5A showing spectrum of a precise isotactic diblock-copolymer(150D-b-150L) showing no errors, FIG. 5B showing spectrum of a gradientisotactic diblock-copolymer (96L-b-(100D+4L)) clearly showingstereoerrors, and FIG. 5C showing spectra of PLLA and several isotacticblock copolymers bearing different block numbers;

FIG. 6 presents X-ray diffraction patterns of selected stereo-n-blocks,with n and block-length of samples are indicated in the labels;

FIG. 7 presents a schematic illustration of a preparation of mononuclearand dinuclear magnesium complexes featuring one or two divergent {ONNN}ligand(s), respectively, according to exemplary embodiments of thepresent invention;

FIG. 8 presents ¹H-NMR spectra (CDC₃, 3-9.5 ppm) of an exemplarymononuclear magnesium complex (top panel, Lig⁴Mg—Cl) and an exemplarydinuclear (bottom panel, [(μ-Lig²)Mg—Cl]₂) magnesium complex, accordingto some embodiments of the present invention.

FIGS. 9A-9B present the crystallographic structures of [(μ-Lig²)Mg—Cl]₂(FIG. 9A) and [(μ-Lig³)Mg—Cl]₂; and

FIG. 10 presents X-ray diffraction patterns of mixtures of homochiralpolymers having about 800 and 1600 repeat units, compared withL(800)-b-D(800) stereo-diblock copolymer.

DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

The present invention, in some embodiments thereof, relates to chemistryand, more particularly, but not exclusively, to block polyestercopolymers, including, but not limited to, stereoblcok polyestercopolymers, featuring high precision, and to one-pot ring openingpolymerization processes for preparing same.

Before explaining at least one embodiment of the invention in detail, itis to be understood that the invention is not necessarily limited in itsapplication to the details of construction and the arrangement of thecomponents and/or methods set forth in the following description and/orillustrated in the drawings and/or the Examples. The invention iscapable of other embodiments or of being practiced or carried out invarious ways.

As discussed hereinabove, the ability to manufacture polymeric materialshaving a ‘tailor-made’ structure is a key-step on the way to improvingthe properties of existing plastics, particularly biodegradable plasticmaterials derived from bio-renewable resources such as poly(lactic acid)(PLA), poly(F-caprolactone) (PCL) and other polyesters.

More advanced PLA generations are expected to include different types oflactide isomers assembled in an ordered (regioregular) fashion, and inparticular block copolymers. In particular, isotactic stereoblock-PLAcomposed of covalently bound PDLA and PLLA blocks has been targeted.

Such tailor-made plastics require sophisticated catalysts, and, in thepast 15 years, there has been an enormous effort to try and develop moreadvanced catalysts.

Some of the requirements of such catalysts are: high activities andturnover numbers leading to high molecular weight-polymers; livingcharacter or possibly immortal character (giving more than a singlepolymer chain for every catalytic center); low cost and low toxicity.

The most controlled manner of producing block copolymers is by employingliving polymerization catalysis. In contrast to non-livingpolymerization which includes the steps of initiation, propagation(chain growth), and termination (with possible growing of a new chain),living polymerization is a process in which only the first two steps,i.e., initiation and propagation, take place. The catalyst is notinvolved in the termination processes. This has several outcomes: (i)all the monomers may be consumed in the process; (ii) if all thecatalyst is activated, and if the propagation is not considerably fasterthan the initiation, then a narrow distribution of molecular weights ofthe polymeric chains is obtained, and the molecular weight of thepolymeric chains can be designed from the ratio of monomer/catalyst ormonomer/initiator employed; (iii) the copolymerization reaction can beresumed upon addition of a new batch of monomers without loss of numberof active catalyst molecules; and (iv) block copolymers may be producedby employing different monomers in different batches.

The most direct strategy for producing block copolymers, andstereoblock-PLA or other stereoblock polyester copolymers in particular,would be the sequential addition of different monomers, e.g., differentlactide enantiomers, to a truly-living polymerization catalyst, namely,a catalyst lacking a termination step.

Currently practiced methodologies for producing stereoblock polyestercopolymers typically require many hours for completion, and are ofteninsufficiently accurate.

As a result, to date, block copolymers of cyclic ester monomers such aslactides and/or lactones are very rare. Moreover, block copolymers, suchas stereoblock copolymers, higher than diblock or triblock copolymers ofcyclic esters, have not been described hitherto.

The present inventors have now devised a novel methodology for preparingblock copolymers of cyclic esters (block polyester copolymers) inextremely short time periods, and in exceptional accuracy (precision).This methodology enables to obtain block polyester copolymers higherthan triblock copolymers, including tetrablock, pentablock, hexablock,and even octablock copolymers, and higher. This methodology furtherenables exceptional controllability on the number of blocks, the length(number of repeating backbone units) of each block, and the number ofpolymeric chains in each block (e.g., number of branches in branchedpolymers).

In some embodiments, the designed methodology may be executed withcatalysts based on biocompatible metals such as magnesium (Mg) and zinc(Zn).

According to an aspect of some embodiments of the present inventionthere are provided processes of preparing block copolymers of cyclicesters.

The Block Copolymers:

Herein, the phrase “block copolymer of a cyclic ester” is also referredto interchangeably as “block polyester copolymer”, describes blockcopolymers comprised of two or more blocks, wherein at least two ofthese blocks comprise, each independently, a polyester homopolymer,wherein the polyester homopolymers in these at least two blocks differfrom one another by their chemical composition and/orstereoconfiguration.

In some embodiments, each block that comprises a polyester homopolymeris comprised of polymerized monomers of a corresponding cyclic ester,and is also referred to herein as a unit in the block copolymer.

Each block is formed of a plurality of cyclic ester monomers whichrepresent a plurality of repeating backbone units covalently attached toone another and forming the homopolymer block.

The term “block” is also referred to herein as “homopolymer block”,“homopolyester block”, “polyester block”, “polyester unit”, “unit” and“unit comprising polymerized monomers of a cyclic ester” (as indicated),and also as combinations of any of the foregoing, and is meant toencompass a unit in the block copolymer that is made of one type ofpolyester, that is, of polymerized monomers of one type of cyclic ester.

A block polyester copolymer can comprise two, three, four, five or moreblocks, and at least two of these blocks are homopolyester blocks whichdiffer from one another by the type (stereoconfiguration and/or chemicalcomposition) of the monomers of the cyclic esters that are polymerizedwithin the block, as described herein.

A block polyester copolymer can comprise two types of blocks (units),each independently comprising (or composed of) a plurality ofpolymerized monomers of a cyclic ester, at least one of these unitscomprises a plurality of polymerized monomers of a first cyclic ester,and at least one another unit of these units comprises a plurality ofpolymerized monomers of a second cyclic ester, the second cyclic esterdiffering from the first cyclic ester by a stereoconfiguration and/or achemical composition, as defined herein.

A block polyester copolymer which comprises two types of blocks cancomprise 2, 3, 4, 5, and more blocks (units), in an alternating order,such that in any pair of adjacent blocks (units), the units are made ofpolymerized monomers of a different cyclic ester.

A block polyester copolymer can comprise three or more types of blocks(units), each independently comprising (or composed of) a plurality ofpolymerized monomers of a cyclic ester, at least one of these unitscomprises a plurality of polymerized monomers of a first cyclic ester,and at least one another unit of these units comprises a plurality ofpolymerized monomers of a second cyclic ester, the second cyclic esterdiffering from the first cyclic ester by a stereoconfiguration and/or achemical composition, as defined herein. Such a block copolymer cancomprise in addition to the above-mentioned units of the first andsecond cyclic ester, units which are not polymerized monomers of acyclic ester (e.g., are rather made of repeating backbone units ofmonomers which are not a cyclic ester). Alternatively, such a blockcopolymer can comprise, in addition to the above-mentioned units of thefirst and second cyclic ester, one or more types of blocks (units), eachindependently comprising (or composed of) a plurality of polymerizedmonomers of a third cyclic ester, and optionally of a fourth cyclicester, while the third cyclic ester is different from the first, secondand, if present, the fourth cyclic esters, and the fourth cyclic esteris different from the first, second and third cyclic esters.

Whenever there are more than two types of blocks (units) in the blockpolyester copolymer, these different blocks can be arranged in anyother.

Non-limiting examples include:

-A-B-A-B-A-B-A-B-

-A-B-C-A-B-C-A-B-C-

-A-B-A-C-A-B-A-C-

-A-B-C-B-A-C-B-C-

-A-B-C-D-A-B-C-D-

-A-C-D-A-B-C-A-D-C-,

Wherein A, B, C and D are each independently a different block, forexample, A is a first type of block (a first unit) made of polymerizedmonomers of a cyclic ester of a first type (a first cyclic ester); B isa second type of block (a second unit) made of polymerized monomers of acyclic ester of a second type (a second cyclic ester); C is a third typeof block (a third unit) made of polymerized monomers of a cyclic esterof a third type (a third cyclic ester), or, alternatively, is a blockmade of polymerized monomers which are not a cyclic ester; and D is afourth type of block (a fourth unit) made of polymerized monomers of acyclic ester of a fourth type (a fourth cyclic ester), or,alternatively, is a block made of polymerized monomers which are not acyclic ester and which different from C.

In some embodiments, the block copolymer is comprised of two types ofblocks, for example, is comprised of a polymer sequence ofBlock-Block2-Block-Block2, wherein Block1 is a polyester of firstchemical composition and/or stereoconfiguration and Block2 is apolyester of a second chemical composition and/or stereoconfigurationwhich is different from the first chemical composition and/orstereoconfiguration.

The copolymer, according to these embodiments, can be a diblock,triblock, tetrablock, etc.

In some embodiments, the block copolymer is comprised of three or moretypes of blocks, which can be sequenced in the block copolymer in anyorder, based on the sequence of subjecting the plurality of cyclic estermonomers forming each block to ring opening polymerization. Thecopolymer, according to these embodiments, can be a triblock,tetrablock, etc.

By “diblock”, “triblock”, “tetrablock”, etc., the number of blocks ispresented. These types of blocks in each of such block copolymers are atleast two, regardless of the number of blocks.

When a block copolymer as described herein comprises two units, it isreferred to as a diblock copolymer.

When a block copolymer as described herein comprises three units (two ofwhich can the same or all three are different), it is referred to astri-block copolymer.

When a block copolymer as described herein comprises four units (two orthree of which can the same or all four are different), it is referredto as tetra-block copolymer, and so forth.

According to some of any of the embodiments described herein, the blockcopolymer comprises 2, 3, 4, 5, 6, 7, 8, 9, 10 or even more units.

According to an aspect of some embodiments of the present inventionthere is provided a block copolymer comprising a plurality of units, atleast two of the plurality of units independently comprise a pluralityof polymerized monomers of a cyclic ester, at least one unit of these atleast two units comprises a plurality of polymerized monomers of a firstcyclic ester, and at least one another unit of these at least two unitscomprises a plurality of polymerized monomers of a second cyclic ester,as described herein, the second cyclic ester differing from the firstcyclic ester by a stereoconfiguration and/or a chemical composition, asdescribed herein.

According to an aspect of some embodiments of the present inventionthere is provided a block copolymer comprising a plurality of units, atleast two adjacent units in said plurality of units independentlycomprise a plurality of polymerized monomers of a cyclic ester, at leastone unit of said at least two adjacent units comprises a plurality ofpolymerized monomers of a first cyclic ester, and at least one anotherunit of said at least two adjacent units comprises a plurality ofpolymerized monomers of a second cyclic ester, said second cyclic esterdiffering from said first cyclic ester by a stereoconfiguration and/or achemical composition.

In some of any of the embodiments described herein, the block copolymerfurther comprises at least one additional unit comprising a plurality ofpolymerized monomers of a third cyclic ester, the third cyclic esterdiffering from each of the first cyclic ester and the second cyclicester by a stereoconfiguration and/or a chemical composition. In someembodiments, the additional unit is adjacent to one and/or both of theat least two adjacent units described hereinabove.

In some of any of the embodiments described herein, the block copolymercomprises from 2 to 10 units, and wherein at least one pair of adjacentunits comprises one unit comprising a plurality of polymerized monomersof said first cyclic ester, and one unit comprising a plurality ofpolymerized monomers of said second cyclic ester, such that the blockcopolymer comprises at least two adjacent units differing from oneanother by a stereoconfiguration and/or a chemical composition.

According to some of any of the embodiments described herein, thepolymerized monomers composing the units in the at least one pair of(e.g., adjacent) units differ from one another by a number ofpolymerized monomers (backbone units) (e.g., a length of the block).That is, for example, in a diblock copolymer, each block is comprised ofa different number of polymerized monomers (backbone units) (a differentnumber of polymerized monomers composing each of the units). In another,non-limiting example, in a triblock copolymer, first block is of Nnumber of backbone units (polymerized monomers), second block is of Mnumber of backbone units (polymerized monomers) and third block is of Lnumber of backbone units (polymerized monomers), wherein either N≠M≠L,or at least N≠M, or M≠L, or N≠L.

In some of any of the embodiments described herein, at least 90%, or atleast 95% or at least 96% or at least 98% or at least 99% of backboneunits (polymerized monomers), or each of the backbone units (polymerizedmonomers), in each of the units (blocks) are identical to one another(feature the same chemical composition and/or stereoconfiguration).

The term “cyclic ester” as used herein describes a —C(═O)—O—Rx in whichRx is a hydrocarbon chain (e.g., lower, medium or higher alkyl,optionally substituted), as defined herein, optionally interrupted byone or more heteroatoms or moieties as defined herein, and one carbonatom of the hydrocarbon chain (e.g., of an alkyl) is linked to thecarbon atom of the carboxylate to form a ring.

In some embodiments, a cyclic ester can be represented by Formula V:

wherein:

Y₁ is selected from oxygen, sulfur and imine (═NR′), preferably fromoxygen and sulfur, and is preferably oxygen;

Y₂ is selected from oxygen, sulfur and —NR′, preferably from oxygen andsulfur, and is preferably oxygen; and

L is a hydrocarbon chain, for example, a hydrocarbon chain whichcomprises one or more alkylene chains, each optionally beingindependently substituted or unsubstituted, and which can optionally beinterrupted therebetween by one or more moieties such as oxygen atom,sulfur atom, amine, silyl, carbonyl, amide, carboxy (—C(═O)—O—),thiocarboxy, thiocarbonyl, and the like.

Each alkylene chain can be of from 1 to 30 carbon atoms, preferably from1 to 20 carbon atoms, or from 1 to 15 carbon atoms, or from 1 to 10carbon atoms.

In some of any of the embodiments described herein, the cyclic estercomprises two or more alkylene chains, which are interruptedtherebetween, wherein at least two alkylene chains are interruptedtherebetween by a carboxy group. Such cyclic esters are also referred toherein and in the art as “cyclic diesters”.

In some of any of the embodiments described herein, the one or morealkylene chain(s) is/are unsubstituted.

In some of any of the embodiments described herein, at least one of Y₁and Y₂ is oxygen.

In some of any of the embodiments described herein, each of Y₁ and Y₂ isoxygen.

In some of any of the embodiments described herein, L is an alkylenechain, non-interrupted. Such cyclic esters are also referred to hereinand in the art as “lactone”.

When Y₂ is —NR′, the cyclic ester is a lactame.

In some of any of the embodiments described herein, L comprises twoalkylene chains, interrupted by a carboxy group, whereby the twoalkylene chains are identical to one another. Such a cyclic diester canalso be regarded as a di-lactone of two molecules of a2-hydroxycarboxylic acid, and is also referred to in the art as lactide.

While the term “lactide” generally describes a dilactone of any2-hydroxycarboxylic acid, herein and in the art, this term typicallyalso refers to a cyclic diester (di-lactone) of lactic acid(2-hydroxypropionic acid), as shown, for example, in Scheme 1hereinabove.

Cyclic esters usable in the context of the present embodiments includesubstituted and unsubstituted lactones such as, for example,caprolactones and lactides, although any other cyclic esters arecontemplated, for example, 6-valerolactone, y-butyrolactone,F-caprolactone, o-pentadecalactone, cyclopentadecanone,16-hexadecanolide, oxacyclotridecan-2-one.

In some of any of the embodiments described herein, the cyclic ester islactide, that is, a di-lactone of lactic acid (2-hydroxypropionic acid).

In some of any of the embodiments described herein, the cyclic ester isa lactone, for example, a caprolactone such as 8-caprolactone.

In some of any of the embodiments described herein, the cyclic ester hasa chiral center.

Herein a “chiral cyclic ester” or a “cyclic ester having a chiralcenter”, typically describes a cyclic ester or a cyclic diester asdefined herein, in which one or more carbon atoms in one or more of thealkylene chains is substituted and thereby form a chiral center.

Whenever these phrases are used, the cyclic ester can be one enantiomer,one diastereomer, a meso form, or a racemic mixture, unless otherwiseindicated.

In some of these embodiments, the cyclic ester is a racemic cyclicester.

In some of any of the embodiments described herein, the cyclic ester islactide and the lactide is a homochiral lactide or a racemic lactide ora meso lactide.

In some of any of the embodiments described herein, the lactide is aracemic lactide.

Herein throughout, the term “chemical composition” refers to thechemical structure of the cyclic ester, that is, the type of atoms andtheir 2D arrangement.

Herein throughout, the term “stereoconfiguration” refers to the spatialarrangement of the atoms in the cyclic ester, and thus refers to cyclicester monomers featuring one or more chiral centers. According to someembodiments, the polymerized monomers feature a stereoconfigurationaccording to the stereoconfiguration of the chiral center(s).

For example, the cyclic monomer can be an enantiomer, and thepolymerized monomers feature an isotactic configuration of theenantiomer. Thus, if a first and a second cyclic ester differ from oneanother by being different enantiomers, a unit comprising polymerizedmonomers of the first cyclic ester exhibits an isotacticstereoconfiguration of this enantiomer, and a unit comprisingpolymerized monomers of the second cyclic ester exhibits an isotacticstereoconfiguration of this enantiomer.

For example, the cyclic monomer can be a diastereoisomer, and thepolymerized monomers feature an isotactic configuration of thediasteroisomer. Thus, if a first and a second cyclic ester differ fromone another by being different diastereomers, a unit comprisingpolymerized monomers of the first cyclic ester exhibits an isotacticstereoconfiguration of this diastereomer, and a unit comprisingpolymerized monomers of the second cyclic ester exhibits an isotacticstereoconfiguration of this diastereomer.

In another example, a first cyclic ester is an enantiomer or adiastereomer and a second cyclic ester is a racemic mixture, a unitcomprising polymerized monomers of the first cyclic ester exhibits anisotactic stereoconfiguration of the enantiomer or diastereomer, and aunit comprising polymerized monomers of the second cyclic ester exhibitsa racemic mixture of the two isotactic stereoconfigurations of theenantiomer or diastereomer. A block comprised of such racemic cyclicester can be heterotactic, isotactically-inclined, gradient isotactic oreven atactic.

Block polyester copolymers featuring at least two units in which thefirst and second cyclic esters differ in their stereoconfiguration arealso referred to herein as “stereoblocks”.

According to an aspect of some embodiments of the present inventionthere is provided a block polyester copolymer as described herein whichis stereoblock copolymer, comprises a plurality (e.g., from 2 to 10) ofunits of polymerized monomers of a cyclic ester, wherein at least twounits (e.g., at least one pair of two adjacent units) comprises one unitcomprising a plurality of polymerized monomers of said first cyclicester featuring a first stereoconfiguration and one unit comprising aplurality of polymerized monomers of said cyclic ester featuring asecond stereoconfiguration, as described herein.

In some of any of the embodiments described herein, the polymerizedmonomers composing the units in at least two units in the copolymer(e.g., in at least one pair of (e.g., adjacent) units, differ from oneanother by a stereoconfiguration.

In some of the embodiments of a stereoblock copolymer as describedherein, the chemical composition of the cyclic ester is the same, thatis, the cyclic ester is the same and the first and second cyclic estersdiffer from one another only by their stereoconfiguration.

In some of any of the embodiments described herein for stereoblocks, atleast 90%, or at least 95% or at least 96% or at least 98% or at least99% of said polymerized monomers in each units comprising same featurethe same stereoconfiguration.

In some of any of the embodiments described herein, the block copolymeris a stereoblock copolymer, as described herein, in which two units inthe block copolymer differ from one another by stereoconfiguration.

In exemplary embodiments, one or more of the cyclic ester monomers is alactide, as described herein.

In exemplary embodiments, one type of cyclic ester monomers (a firstcyclic ester) is a lactide having one stereoconfiguration and anothertype of cyclic ester monomers (a second cyclic ester) is a lactidehaving another stereoconfiguration, and/or is another cyclic ester(e.g., a glycolide or a lactone).

In exemplary embodiments, the block copolymer is made of two or moretypes of lactides, which differ from one another in stereoconfiguration,and optionally, one type of monomers comprises glycolide.

In exemplary embodiments, the block copolymer is made of two or moretypes of lactides, which differ from one another in stereoconfiguration,and optionally, one type of monomers comprises a lactone.

In exemplary embodiments, the block copolymer is made of one or moretypes of lactides, and one type of monomers of a lactone.

In exemplary embodiments, the lactone is a caprolactone.

Exemplary such block copolymers include, but are not limited to:PLLA-PDLA, PDLA-PLLA-PDLA, PDLA-PLLA-PDLA-PLLA, and so forth,PLLA-PDLA-glycolide; PLLA-glycolide-PLDA-glycolide;PLLA-PDLA-glycolide-PLLA-PDLA-glycolide; PLLA/PDLA-glycolide-PDLA/PLLA;PLLA/PDLA-glycolide-PDLA/PLLA-glycolide, PLLA-PDLA-PCL,PLLA-PDLA-PCL-PDLA-PLLA, PCL-PLLA-PDLA-glycolide and any othercombinations of two or all of PLLA, PDLA, glycolide andpolycaprolactone.

In some of any of the embodiments described herein, the block copolymersof a cyclic ester are obtainable by a process as described herein in anyof the respective embodiments.

In some of any of the embodiments described herein, there is provided ablock copolymer of a cyclic ester comprising a plurality of units, atleast two of said units independently comprise a plurality ofpolymerized monomers of a cyclic ester, wherein one of said at least twounits comprises a plurality of polymerized monomers of a first cyclicester and a another one of said at least two units comprises a pluralityof polymerized monomers of a second cyclic ester, said first cyclicester and said second cyclic ester differ from one another by a chemicalcomposition and/or a stereoconfiguration, wherein:

at least 90%, or at least 95% or at least 96% or at least 98% or atleast 99% of the polymerized monomers (backbone units) in each of theunits are identical to one another, as described herein; and/or

a number of the polymerized monomers in at least two of the units isdifferent in each of the at least two units; and/or

the block copolymer comprises at least 3, or at least 4 units ofpolymerized monomers of the cyclic ester.

In some of any of the embodiments described herein, there is provided ablock copolymer of a cyclic ester comprising at least two units ofpolymerized monomers of a cyclic ester, wherein at least one, or each,pair of adjacent units comprises a first unit of polymerized monomers ofa first type and a second unit of polymerized monomers of a second type,the monomers of the second type differing from the monomers of the firsttype by a chemical composition and/or a stereoconfiguration of thecyclic ester, wherein:

at least 90%, or at least 95% or at least 96% or at least 98% or atleast 99% of the polymerized monomers (backbone units) in each of theunits are identical to one another; and/or

a number of the polymerized monomers in at least two of the units isdifferent in each of the at least two units; and/or the block copolymercomprises at least 3, or at least 4 units of polymerized monomers of thecyclic ester.

In some of any of the embodiments described herein, the cyclic estercomprises at least one stereocenter and wherein at least two of theunits differ from one another by a stereoconfiguration of the cyclicester.

In some of any of the embodiments described herein, the cyclic ester islactide.

In some of any of the embodiments described herein, the cyclic ester isF-caprolactone.

In some of any of the embodiments described herein, each of the unitsindependently comprises polymerized monomers featuring a polymericconfiguration selected from a linear polymeric chain and branchedpolymeric chains, as described herein in further detail regardingpolyalcohols as initiators.

In some of any of the embodiments described herein, the block copolymeris characterized by a polydispersity (Mw/Mn) lower than 1.5, or lowerthan 1.2.

In some of any of the embodiments described herein, the block copolymeris characterized by characterized by a Tm of at least 200° C.

In some of any of the embodiments described herein, the block copolymeris characterized by a substantial heat of melting of at least 40 J/g, or50 J/g, or 60 J/g, or 70 J/g, or 80 J/g.

Any of the block copolymers described herein are contemplated.

In some of any of the embodiments described herein, the block polyestercopolymers described herein are obtainable by a ring openingpolymerization as described herein, and is some embodiments, the ringopening polymerization is an isoselective polymerization (e.g., in casethe cyclic ester is chiral). By “isoselective polymerization”, it ismeant a stereo-controlled polymerization that provides at least oneenchainment of an identical enantiomer or diastereomer. Isoselectivepolymerization can provide a polymer comprising backbone units thatfeature generally (e.g., at least 60%, or at least 70%, or at least 80%,or more) the same stereoconfiguration, that is a single enchainment ofan identical enantiomer or diastereomer, or a mixture of two suchpolymers (for example, one of an R enantiomer and the other of an Senantiomer).

Isoselective polymerization can be determined by the Pm of the obtainedpolymer.

Herein and in the art, Pm describes the tendency for a meso-enchainment(i.e. identical enantiomer enchainment) in polymerization of a cyclicester having one or more chiral centers, which gives rise to isotacticpolyester. A Pm value of 1.0 corresponds to perfectly isotacticpolyester and a Pm value of 0.5 or lower corresponds to atactic PLA. APm value higher than 0.6, or higher than 0.7 is indicative of anisoselective polymerization.

In some of any of the embodiments described herein, one type of thecyclic esters is a racemic mixture of a chiral cyclic ester, and theblock obtained therefrom is characterized by Pm of at least 0.6, or atleast 0.7, or at least 0.8, while higher values are also contemplated.

According to an aspect of some embodiments of the present inventionthere is provided an article-of-manufacturing comprising a blockpolyester copolymer as described herein in any of the respectiveembodiments. Any articles commonly containing polylactides and/orpolyglycolides and/or polycaprolactones are contemplated, asrepresentative, non-limiting examples. Examples include, withoutlimitation, commodity articles like food packaging, fibers, tubes,non-woven fabrics, etc. and articles employed in biomedical applicationslike resorbable coronary stents, matrices for controlled drug release,implants, sutures, etc.

The Process:

According to an aspect of some embodiments of the present inventionthere is provided a process of preparing any of the block polyestercopolymers as described herein in any of the respective embodiments andany combination thereof.

According to some of any of the embodiments of the present invention theprocess comprises sequentially subjecting a plurality of monomers of afirst cyclic ester, a second cyclic ester, and optionally a third,fourth and so forth cyclic esters, to conditions for effectingring-opening polymerization of the cyclic ester. This results insequential units in the block copolymer, each being a homopolymer formedof a plurality of cyclic ester monomers, which differ from one another,in each unit, by chemical composition and/or stereoconfiguration,according to the selected cyclic esters and the sequencing of subjectingsame to the polymerization conditions.

According to some of any of the embodiments described herein, thesequentially subjecting comprises sequentially contacting a plurality ofmonomers of the cyclic ester composing each of the units of polymerizedmonomers with a catalyst system for effecting the ring openingpolymerization.

According to some of any of the embodiments described herein, thesequential contacting comprises contacting a plurality of monomers of afirst type (featuring a first stereoconfiguration and/or a firstchemical composition; a first cyclic ester) with the catalyst system fora first time period; and, subsequent to the first time period,contacting a plurality of monomers of a second type (featuring a secondstereoconfiguration and/or a second chemical composition; the secondstereoconfiguration being different from the first stereoconfigurationand/or the second chemical composition being different from the firstchemical composition; a second cyclic monomer), for a second timeperiod, and, optionally, subsequent to the second time period,contacting an additional plurality of monomers, being either of thefirst type or of a third type (which differs from the first and secondtype by a chemical composition and/or stereoconfiguration), for a thirdtime period; and, further optionally, subsequent to the third timeperiod, contacting a plurality of monomers of a type different from thethird type (e.g., either the second type or a fourth type), for a fourthtime period, and, further optionally, repeating contacting plurality ofmonomers of the first, second, third, fourth or other type, foradditional time periods, according to a desirable number of block typesand a desirable number of units in the block copolymer.

According to some of any of the embodiments described herein, each ofthe time periods independently ranges from 1 minute to 6 hours, or from1 minute to 3 hours, or from 1 minute to 2 hours, or from 1 minute toone hour, or from 1 minute to 30 minutes, or from 5 minutes to 30minutes or from 5 minutes to 20 minutes, including any intermediatevalues and subranges therebetween.

According to some of any of the embodiments described herein, thesequential addition can be effected also within higher time intervals,in view of the living nature of the catalyst.

According to some of any of the embodiments described herein, theprocess is a one-pot process (such that the sequential subjectingcomprises sequentially adding the plurality of monomers to a reactionvessel containing the conditions for effecting ROP (e.g., containing thecatalyst system and optionally a solvent).

In exemplary embodiments, one type of cyclic ester monomers is alactide, as described herein.

In exemplary embodiments, one type of cyclic ester monomers is a lactidehaving one stereoconfiguration and another type of cyclic ester monomersis a lactide having another stereoconfiguration, and/or is anothercyclic ester (e.g., a glycolide).

In exemplary embodiments, the block copolymer is made of two or moretypes of lactide, which differ from one another in stereoconfiguration,and optionally, one type of monomers comprises glycolide.

In some of any of the embodiments described herein, the block copolymeris a diblock copolymer, and the diblock copolymer is obtained withinless than 2 hours, or less than one hour.

In some of any of the embodiments described herein, the ring openingpolymerization is effected by sequentially contacting a plurality ofmonomers of a first, second and so for the cyclic esters with a catalystsystem for effecting ROP of the cyclic ester.

In some of any of the embodiments described herein, The catalyst systemcomprises an organometallic complex as described herein in any of therespective embodiments.

The organometallic complex as described herein in any of the respectiveembodiments is also referred to herein as a “catalyst” or, in someembodiments, as a “pre-catalyst”, which is activated by a co-catalyst asdescribed herein. In some of any of the embodiments described herein,the catalyst system further comprises a co-catalyst.

The “co-catalyst” described herein is also referred to herein and in theart as “initiator”.

In some embodiments, the initiator is a hydroxy-containing compound.

The hydroxy-containing compound can feature one hydroxy group, and canbe, for example, HO-Rk, wherein Rk is alkyl, alkaryl, cycloalkyl oraryl, each can optionally be substituted or unsubstituted, as describedherein.

Exemplary such initiators include, without limitation, benzyl alcohol,and alkyl alcohols such as ethyl alcohol, methyl alcohol, 2-propylalcohol, tert-butyl alcohol, monohydroxy terminated polyethylene glycol,and monohydroxy terminated pre-synthesized polymers.

The hydroxy-containing compound can feature two or more hydroxy groups,and such compounds are also referred to herein and in the art aspolyhydroxy or polyalcohol compounds.

Exemplary such compounds include, but are not limited to, alkyleneglycols (featuring 2 hydroxy groups, for example, ethylene glycol,propylene glycol, etc., as glycerols (featuring 3 hydroxy groups),higher linear saccharides, and polyhydroxy compounds such poly(ethyleneglycol) or pentaerythritol.

The type of initiator, namely, the number of the hydroxy groups in theinitiator determines the number of the polymeric chains in a block(unit) of polymerized cyclic ester monomers.

For example, linear block copolymers are obtained when monohydroxyinitiator is employed. Two polymeryl chains are grown in parallel when adihydroxy initiator is employed. Star-shapes and comb-shaped blockcopolymers are obtained while employing multihydroxy initiator with arespective distribution of the hydroxy groups.

In some embodiments, the initiator forms a part of the block copolymer,as the core from which the blocks are grown by the sequential formationof the homopolymers in each block.

A mol ratio of the cyclic ester and the initiator determines the numberof backbone units in each polymeric chain.

Thus, the architecture of each unit (e.g., number and length of thepolymeric chains in each block) can be determined or controlled asdesired by using an initiator that provides for the desirableproperties.

In some of any of the embodiments described herein, the catalyst systemdoes not comprise a co-catalyst, and in some of these embodiments, thecatalyst system consists of the organometallic complex. In some of theseembodiments, M in Formula I or IA is magnesium (Mg). In some of theseembodiments, X in Formula I or IA is halo (e.g., chloro). In some ofthese embodiments, X in Formula I or IA is a substituted amine, asdescribed herein, for example, HMDS.

In some of any of the embodiments described herein, the sequentialcontacting is at room temperature.

In some of any of the embodiments described herein, the sequentialcontacting is in a solution (e.g., in an organic solvent). In someembodiments, the organic solvent is a polar solvent, for example, havinga polarity index higher than 1, or higher than 2, or higher than 3, andin some embodiments, it is a polar aprotic solvent. In some embodiments,the organic solvent is devoid of heteroatoms that can coordinate themetal atom, such as oxygen and nitrogen.

Exemplary solvents include, but not limited to, dichloromethane (DCM),chlorobenzene, tetrahydrofuran (THF), diethylether, ethylene dichloride,toluene, pentane, and the like.

In some of any of the embodiments described herein, the sequentialcontacting is in a melt, that is, is devoid of a solvent and isperformed at a temperature at which the cyclic esters are liquid, forexample, at a temperature which is at least the melting temperature ofthe cyclic ester, or is higher than the melting temperature of thecyclic ester by, for example, 5, 10, 15, 20 or more ° C.

In some of any of the embodiments described herein, the sequentialcontacting is effected under inert environment.

By “inert environment” it is meant an environment that is substantiallyfree of oxygen, carbon dioxide, water and/or any other substances thatmay chemically react with the organometallic complex or otherwiseinterfere in the polymerization reaction.

In some of any of the embodiments described herein, the sequentialcontacting is for a total time period that ranges from 1 second to 24hours, or from 1 second to 12 hours, or from 1 second to 5 hours, orfrom 10 seconds to 5 hours, or from 30 seconds to 5 hours, or from 30seconds to 3 hours, of from 30 seconds to 2 hours, including anyintermediate values and subranges therebetween, and depending on thenumber of blocks in the block copolymer.

In some of any of the embodiments described herein, a mol ratio of thecyclic ester and the organometallic complex ranges from 10:1 to100000:1, or from 100:1 to 100000:1, or from 100:1 to 10000:1, includingany intermediate values and subranges therebetween.

In some of any of the embodiments described herein, a mol ratio of theorganometallic complex and the co-catalyst (if present) ranges from1000:1 to 1:1000, or from 100:1 to 1:100, or from 10:1 to 1:1000, orfrom 10:1 to 1:100, or from 10:1 to 1:50, or from 10:1 to 1:40 or from10:1 to 1:30, or from 10:1 to 1:20 or from 10:1 to 1:10, or from 1:1 to1:10, or from 1:1 to 1:8, or from 1:1 to 1:6, or from 1:1 to 1:5 or from1:1 to 1:4, including any intermediate values and subrangestherebetween.

In some of any of the embodiments described herein, the polymerizationis a living polymerization.

By “living polymerization”, as used herein, it is meant a form of chaingrowth polymerization where chain termination is very low, the molecularweight of the polymer is proportional to the conversion, and themolecular weight distribution, PDI (polydispersity index), is verynarrow.

In some of any of the embodiments described herein, the polymerizationis an immortal polymerization.

Immortal polymerization, as used herein, is a form of living chaingrowth polymerization where the number of polymer chains is higher thanthe number of catalyst molecules and all polymer chains can grow by thecatalyst. For example, by employing a ratio of a co-catalyst to livingcatalyst higher than 1 the number of polymer chains will be higher thanthe number of catalyst molecules and identical to the number ofco-catalyst molecules. As a result, immortal polymerization can affordpolymers with a controlled molecular weight, while the number of polymermolecules is higher than the number of the catalyst molecules.

In some of any of the embodiments described herein, the process iseffected while employing a catalyst system which comprises an initiatorand a {ONNN}M-X organometallic complexes, wherein M is a divalent metal,as described herein, and X is a monoanionic ligand as described herein,in any of the respective embodiments and any combination thereof.

In some of any of the embodiments described herein, a mol ratio of theorganometallic complex and the initiator ranges from 1:1 to 1:1000.

In some of any of the embodiments described herein, a mol ratio of thecyclic ester and the initiator determines the number of backbone unitsin each of the units of polymerized monomers of the cyclic ester.

In some of any of the embodiments described herein, a process asdescribed herein in any of the respective embodiments is of preparing astereoblock polyester copolymer as described herein in any of therespective embodiments.

In some of these embodiments, the process comprises:

sequentially contacting a plurality of monomers of the cyclic esterfeaturing the first stereoconfiguration and a plurality of monomers ofthe cyclic ester featuring the second stereoconfiguration with acatalyst system as described herein in any of the respectiveembodiments.

In some embodiments, the catalyst system comprises an initiator and a{ONNN}M-X complex, as described herein in any of the respectiveembodiments.

In some of any of the embodiments described herein, the sequentialcontacting comprises contacting the plurality of monomers featuring thefirst stereoconfiguration with the catalyst system for a first timeperiod; and, subsequent to the first time period, contacting theplurality of monomers featuring the second stereoconfiguration for asecond time period, and, optionally, subsequent to the second timeperiod, contacting the plurality of monomers featuring the firststereoconfiguration with the catalyst system for a third time period;and, further optionally, subsequent to the third time period, contactingthe plurality of monomers featuring the second stereoconfiguration for afourth time period, and, further optionally, repeating each of thecontacting for additional time periods, according to the number of unitsin the stereoblock copolymer.

In some of any of the embodiments described herein, each of the timeperiods independently ranges from 1 minute to 6 hours, or from 1 minuteto 3 hours, or from 1 minute to 2 hours, or from 1 minute to 1 hour, orfrom 1 minute to 30 minutes, or from 5 minutes to 30 minutes or from 5minutes to 20 minutes, including any intermediate values and subrangestherebetween.

In some of any of the embodiments described herein, the process is aone-pot process (such that the sequential addition is performed bysequentially adding the plurality of monomers to a reaction vesselcontaining the catalyst system and optionally a solvent).

The Catalyst System:

In some of any of the embodiments described herein, the catalysts systemcomprises an organometallic complex comprising a tetradentatemonoanionic {ONNN}-type ligand and a divalent metal.

In some of these embodiments, the tetradentate monoanionic {ONNN}-typeligand, also referred to herein simply as a {ONNN} ligand is asequential {ONNN} as described herein in any of the respectiveembodiments, and as represented, for example, by Formula I or Formula IAherein.

In some of these embodiments, the {ONNN} ligand a divergent {ONNN}ligand as described herein in any of the respective embodiments, and asrepresented, for example, by Formulae IIA, IIB, and III herein.According to some of any of the embodiments of the present invention theorganometallic complex features a sequential {ONNN} ligand isrepresented by Formula I:

wherein:

the dashed line represents a coordinative bond;

M is a divalent metal;

X is a monoanionic ligand;

A, B_(A) and B_(B) are each independently a bridging moiety of 1 to 20or of 1 to 12 carbon atoms;

R₁ and R₂ are each independently hydrogen, alkyl, cycloalkyl, aryl oralternatively, one or both of R₁ and R₂ form together, optionally withone or more carbon atoms in A, a heteroalicyclic or heteroaromatic, 5 to7-membered ring; and

R₃ and R₄ are each independently hydrogen, alkyl, cycloalkyl, aryl oralternatively, one or both of R₃ and R₄ form together with one or morecarbon atoms in B₂, a heteroalicyclic or heteroaromatic, 5 to 7-memberedring.

By “divalent metal” it is meant a metal that has a valency of 2, thatis, is capable of forming two covalent bonds with 2 monovalent atoms. A“divalent metal” encompasses also metals which feature also highervalency.

In some of any of the embodiments described herein, M is zinc,magnesium, or calcium. Other divalent metals are also contemplated. Insome preferred embodiments, M is zinc.

In some preferred embodiments, M is magnesium.

The monoanionic ligand, X, can be, as non-limiting examples, alkyl(substituted or unsubstituted), cycloalkyl (substituted orunsubstituted), aryl (substituted or unsubstituted), amide, alkoxy,thioalkoxy, aryloxy, thioalryloxy, halo or amine (substituted orunsubstituted), as these terms are defined herein.

In some of any of the embodiments described herein for Formula I, M iszinc, and X is alkyl, alkaryl, cycloalkyl or aryl. In some of theseembodiments, X is alkyl, preferably an unsubstituted alkyl, for example,ethyl. Other alkyls, preferably lower alkyls, are contemplated.

In some of any of the embodiments described herein for Formula I, M ismagnesium and X is halo, for example chloro.

In some of any of the embodiments described herein for Formula I, M ismagnesium and X is amine. In some of these embodiments, the amine is asubstituted amine (e.g., a secondary or tertiary amine), (e.g., a mono-or di-substituted amine) and in some embodiments the amine is a tertiaryamine, substituted by two substituents, as defined hereinunder for R andR″.

In exemplary embodiments of Formula I, M is magnesium and X is an aminesubstituted by one or two silyl groups, as defined herein. In some ofthese embodiments, the one or two silyl groups are independentlysubstituted, for example, by one or more alkyl groups.

In exemplary embodiments of Formula I, M is magnesium and X isbis-trimethylsilyl-amino of the formula: [(CH₃)₃Si]₂N—, which is alsoreferred to herein and in the art as HMDS.

It is noted that when an amine is bound to a metal atom, the resultingmoiety is also referred to herein and in the art as “amide”, that is, aM-NR′R″ moiety as described herein is also referred to herein and in theart as a metal amide (e.g., Mg-HMDS amide.

In some embodiments, catalyst systems in which X is an amine or amide asdefined herein are usable in polymerization of block copolymers in whichone of the cyclic monomers is caprolactone.

In some embodiments, catalyst systems in which X is a halo as definedherein (e.g., chloro) are usable in polymerization of block copolymersin which the cyclic monomers are lactides.

Any one of the bridging moieties, A, B_(A) and B_(B), independently, canbe a hydrocarbon chain of the indicated number of carbon atoms, asdefined herein.

Herein, the term “hydrocarbon” describes an organic moiety thatincludes, as its basic skeleton, a chain of carbon atoms, also referredto herein as a backbone chain, substituted mainly by hydrogen atoms. Thehydrocarbon can be saturated or unsaturated, be comprised of aliphatic,alicyclic and/or aromatic moieties, and can optionally be substituted byone or more substituents (other than hydrogen). A substitutedhydrocarbon may have one or more substituents, whereby each substituentgroup can independently be, for example, alkyl, cycloalkyl, alkenyl,alkynyl, alkaryl, aryl, heteroaryl, heteroalicyclic, amine, halo,sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy,thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, azide,sulfonamide, carboxy, thiocarbamate, urea, thiourea, silyl, carbamate,amide, and hydrazine, and any other substituents as described herein.

In some embodiments, the hydrocarbon is substituted by one or moreamine-containing groups, such as amide, alkyl, alkaryl, aryl orcycloalkyl substituted by one or more amine groups, an amine-containingheteroalicyclic, and/or an amine-containing heteroaryl.

The hydrocarbon moiety can optionally be interrupted by one or moreheteroatoms, including, without limitation, one or more oxygen, nitrogen(substituted or unsubstituted, as defined herein for —NR′—) and/orsulfur atoms.

In some embodiments of any of the embodiments described herein thehydrocarbon is not interrupted by any heteroatom, nor does it compriseheteroatoms in its backbone chain, and can be an alkylene chain, or becomprised of alkyls, cycloalkyls, aryls, alkenes and/or alkynes,covalently attached to one another in any order.

In some of any of the embodiments described herein, the hydrocarbon isan alkylene chain, which can be unsubstituted or substituted, asdescribed herein.

In some of any of the embodiments described herein, the B_(A) bridgingmoiety has a general Formula:—(CRaRb)m-C(R₁₇R₈)—C(R₁₉R₂₀)—

wherein:

m is an integer of from 1 to 6, or from 1 to 4, or from 1 to 2;

Ra and Rb are each independently hydrogen, alkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxyl, alkoxy, thiol, thioalkoxy,aryloxy, and amine, wherein when m is other than 1, Ra and Rb in each(CRaRb) unit can be the same or different, and one or both Ra and Rb inone unit can form a 5-, 6- or 7-membered alicyclic, heteroalicyclic,aromatic or heteroaromatic ring with one or both Ra and Rb of anadjacent unit; and R₁₇-R₂₀ are each independently hydrogen, alkyl,cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxyl, alkoxy, thiol,thioalkoxy, aryloxy, and amine, or, alternatively, two or more ofR₁₇-R₂₀ form together a 5-, 6- or 7-membered alicyclic, heteroalicyclic,aromatic or heteroaromatic ring.

In some of these embodiments m is 1.

In some of any of the embodiments of B_(A) of the above formula, Ra andRb are each hydrogen.

In some of any of the embodiments of B_(A) of the above formula, R₁₇-R₂₀form together a substituted or unsubstituted, preferably 6-membered,aromatic ring.

In some of any of the embodiments of B_(A) of the above formula, R₁₇-R₂₀form together with the oxygen attached to B_(A) a substituted orunsubstituted phenolate group.

In some of any of the embodiments described herein, the B_(B) bridgingmoiety has a general Formula:—(CRcRd)n-C(R₂₁R₂₂)—

wherein:

n is an integer of from 1 to 6, or from 1 to 4, or from 1 to 2;

Rc and Rd are each independently hydrogen, alkyl, cycloalkyl, alkaryl,aryl, heteroaryl, heteroalicyclic, hydroxyl, alkoxy, thiol, thioalkoxy,aryloxy, and amine, wherein when n is other than 1, Rc and Rd in each(CRcRd) unit can be the same or different, and one or both Rc and Rd inone unit can form a 5-, 6- or 7-membered alicyclic, heteroalicyclic,aromatic or heteroaromatic ring with one or both Re and Rd of anadjacent unit; and

R₂₁ and R₂₂ are each independently hydrogen, alkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxyl, alkoxy, thiol, thioalkoxy,aryloxy, and amine, or, alternatively, at least two of R₃, R₄, R₂₁ andR₂₂ form together a 5, 6- or 7-membered heteroalicyclic orheteroaromatic ring (which includes, as a heteroatom, at least thenitrogen to which B_(B) is attached, thus forming a nitrogen-containingheteroalicyclic or heteroaryl, as described herein).

In some of any of these embodiments, n is 1.

In some of any of these embodiments, Rc and Rd are each hydrogen.

In some of any of these embodiments, R₃, R₄, R₂₁ and R₂₂ form together asubstituted or unsubstituted, preferably 6-membered, heteroaromaticring, for example, a nitrogen-containing hereteroaryl, as describedherein. In some of these embodiments, the heteroaryl is pyridine, whichis connected to (CRcRd)n at the ortho position. Other heteroaryls, orheteroalicyclics, and other attachment positions are also contemplated.

In some of any of the embodiments described herein, the complex isrepresented by Formula IA:

wherein M, X, A, R₁, R₂, n, m, and Ra-Rd, are as defined herein in anyof the respective embodiments, and

R₂₃-R₃₀ are each independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl, alkaryl, aryl, halo, alkoxy, aryloxy, silyl(e.g., trialkylsilyl), heteroalicyclic, heteroaryl, and amine, and anyof the other substituents described herein.

In some of any of the embodiments pertaining to Formula IA, at least oneof R₂₃-R₂₆ is alkyl.

In some of any of the embodiments pertaining to Formula IA, at least oneof R₂₄ and R₂₆ is alkyl.

In some of any of the embodiments pertaining to Formula IA, the alkyl isa bulky alkyl such as, but not limited to, tert-butyl, isobutyl,isopropyl, trityl, cumyl and tert-hexyl.

As used herein, the phrase “bulky”, in the context of a group or analkyl in particular, describes a group that occupies a large volume. Abulkiness of a group or an alkyl is determined by the number and size ofthe atoms composing the group, by their arrangement, and by theinteractions between the atoms (e.g., bond lengths, repulsiveinteractions). Typically, lower, linear alkyls are less bulky thanbranched alkyls; bicyclic molecules are more bulky than cycloalkyls,etc.

Exemplary bulky alkyls include, but are not limited to, branched alkylssuch as tert-butyl, isobutyl, isopropyl and tert-hexyl, as well assubstituted alkyls such as triphenylmethane (trityl) and cumyl.

In some of any of the embodiments pertaining to Formula IA, at least oneof R₂₃-R₂₆ is independently a halo, for example, chloro, bromo or iodo,preferably chloro.

In some of any of the embodiments pertaining to Formula IA, at least oneof R₂₄ and R₂₆ is halo (e.g., chloro).

In some of any of the embodiments pertaining to Formula IA, at least oneof R₂₃-R₂₆ is a bulky rigid group.

The bulky rigid group can be, for example, aryl, heteroaryl, cycloalkyland heteroalicyclic, having at least 7 carbon atoms.

As used herein, the phrase “bulky rigid group” describes a bulky group,as defined herein, with reduced number of free-rotating bonds. Such agroup, unlike bulky alkyls, are rigid in terms of free rotation.Exemplary bulky rigid groups that are suitable for use in the context ofembodiments of the invention include, but are not limited to, aryl,heteroaryl, cycloalkyl and/or heteroalicyclic, as defined herein.

In some embodiments, the rigid bulky group is such that has a total of 7carbon atoms or more, each being substituted or unsubstituted.

In some embodiments, the bulky rigid group is a bicyclic group,comprising two or more of a cycloalkyl, aryl, heteroalicyclic orheteroaryl fused or linked to one another.

An exemplary bulky rigid group is adamantyl, for example, 1-adamantyl.

In some of any of the embodiments pertaining to Formula IA, R₂₆ is abulky rigid group, as defined herein, for example, 1-adamantyl.

In some of any of the embodiments pertaining to Formula IA, each ofR₂₇-R₃₀ is hydrogen, although any other substituents are contemplated.

In some of any of the embodiments pertaining to Formula IA, at least oneof R₂₇-R₃₀ is a heteroalicyclic or a heteroaryl, preferably anitrogen-containing heteroalicyclic or heteroaryl, as described herein.In some of these embodiments, the additional nitrogen atom alsocoordinates with the metal atom M, such the complex comprises apentadentate ligand.

In some of any of the embodiments pertaining to Formula IA, R₃₀ is anitrogen-containing heteroaryl, and in some of these embodiments, thecomplex comprises a pentadentate ligand.

In some of any of the embodiments described herein for Formula I or IA,R₁ and R₂ can be the same or different and each is independently analkyl, an aryl or an alkaryl (e.g., benzyl). In exemplary embodiments,R₁ and R₂ are each alkyl, for example, are each methyl. In exemplaryembodiments, R₁ and R₂ are each alkaryl, for example, benzyl.

In some of any of the embodiments described herein for Formula I or IA,one or both of R₁ and R₂ form together with one or more carbon atoms inA, a heteroalicyclic 5-, 6- or 7-membered ring.

In some of any of the embodiments described herein for Formula I or IA,at least one of R₁ and R₂ do/does not form together with one or morecarbon atoms in A, a heteroalicyclic 5-, 6- or 7-membered ring.

In some of any of the embodiments described herein for Formula I or IA,at least one of R₁ and R₂ do/does not form together with one or morecarbon atoms in A, a pyrrolidone ring.

In some of any of the embodiments described herein for Formula I or IA,A is other than bispyrrolidone.

In some of any of the embodiments described herein, for Formula I andIA, the A bridging moiety has a general Formula A1, A2 or A3:—C₁R₅R₆—  Formula A1—C₁(R₇R₈)—C₂(R₉R₁₀)—  Formula A2—C₁(R₁₁R₁₂)—C₂(R₁₃R₁₄)—C₃(R₁₅R₁₆)—  Formula A3

wherein R₅-R₁₂, R₁₅ and R₁₆ are each independently selected from thegroup consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl andheteroalicyclic,

R₁₃ and R₁₄ are each independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic,hydroxyl, alkoxy, thiol, thioalkoxy, aryloxy, and amine or any of theother substituents described herein, or, alternatively,

at least two of R₁, R₂ and R₅-R₆ in Formula A1, or at least two of R₁,R₂ and R₇-R₁₀ in Formula A2 or at least two of R₁, R₂ and R₁₁-R₁₆ inFormula A3 form a 5-, 6- or 7-membered alicyclic, heteroalicyclic,aromatic or heterocyclic ring.

In some of any of the embodiments described herein, in formula A1, eachof R₅ and R₆ is hydrogen, that is, A is methylene.

In some of any of the embodiments described herein, in formula A2, eachof R₇-R₁₀ is hydrogen, that is, A is ethylene.

In some of any of the embodiments described herein, in formula A3, eachof R₁₁-R₁₆ is hydrogen, that is, A is propylene.

In some of the embodiments where the bridging moiety A is an alkylenechain (methylene, ethylene or propylene), R₁ and R₂ can be the same ordifferent and each is independently an alkyl, an aryl or an alkaryl(e.g., benzyl). In exemplary embodiments, R₁ and R₂ are each alkyl, forexample, are each methyl. In exemplary embodiments, R₁ and R₂ are eachalkaryl, for example, benzyl.

In some of any of the embodiments described herein, the bridging moietyhas the Formula A2.

In some of any of the embodiments described herein, in formula A2, eachof R₇-R₁₀ is hydrogen. In some of these embodiments, R₁ and R₂ can bethe same or different and each is independently an alkyl, an aryl or analkaryl (e.g., benzyl). In exemplary embodiments, R₁ and R₂ are eachalkyl, for example, are each methyl. In exemplary embodiments, R₁ and R₂are each alkaryl, for example, benzyl.

In some of any of the embodiments described herein, in formula A2, R₇and R₁ form the heteroalicyclic ring, for example, a pyrrolidine.

Alternatively, or in addition, in some embodiments, R₉ and R₂ form theheteroalicyclic ring, for example, a pyrrolidine.

In some of any of the embodiments described herein for formula A2, thebridging moiety is bipyrrolidine.

In some of any of the embodiments described herein, at least one, orboth, of R₁ and R₂ is independently an alkyl, for example, methyl.

Exemplary, non-limiting examples of complexes according to the presentembodiments are presented in the Examples section that follows.

In some of any of the embodiments described herein, the catalyst systemfurther comprises an initiator and in some embodiments the initiator isa hydroxy-containing compound, as described herein.

The hydroxy-containing compound can feature one hydroxy group, and canbe, for example, HO-Rk, wherein Rk is alkyl, cycloalkyl or aryl.

Exemplary such initiators include, without limitation, benzyl alcohol,and alkyl alcohols such as ethyl alcohol, methyl alcohol, 2-propylalcohol, tert-butyl alcohol, and monohydroxy terminated polyethyleneglycol.

The hydroxy-containing compound can feature two or more hydroxy groups,and such compounds are also referred to herein and in the art aspolyhydroxy compounds.

Exemplary such compounds include, but are not limited to, alkyleneglycols (featuring 2 hydroxy groups, for example, ethylene glycol,propylene glycol, etc., as glycerols (featuring 3 hydroxy groups),higher linear saccharides, and polyhydroxy compounds such poly(ethyleneglycol) or pentaerythritol.

The type of initiator, namely, the number of the hydroxy groups in theinitiator determines the number of the polymeric chains in each of theunits of polymerized monomers of the cyclic ester.

A mol ratio of the cyclic ester and the initiator determines the numberof backbone units in each of the units of polymerized monomers in theblock copolymer

Thus, the polymer architecture (e.g., number and length of the polymericchains) can be determined or controlled as desired by using an initiatorthat provides for the desirable properties.

Catalysts Systems Featuring a Divergent {ONNN} Ligand:

According to an aspect of some embodiments of the present invention,there is provided a process of ring opening polymerization of a cyclicester, the process comprising contacting the cyclic ester with acatalyst system that comprises an organometallic complex featuring adivergent {ONNN} ligand as described herein in any of the respectiveembodiments. In some of these embodiments, the polymerization is anisoselective polymerization as described herein,

According to an aspect of some embodiments of the present invention,there is provided a process of preparing a block polyester copolymer asdescribed herein, wherein the polymerization is effected by sequentiallycontacting the cyclic ester monomers with a catalyst system thatcomprises an organometallic complex featuring a divergent {ONNN} ligandas described herein in any of the respective embodiments.

The processes parameters, the cyclic ester, the obtained copolymers andthe catalyst system are as described herein in any of the respectiveembodiments.

According to some of any of the embodiments described herein, theorganometallic magnesium complex featuring a divergent ligand comprisesa Mg—X unit (e.g., one or two such units) and a divergent {ONNN} ligandin coordination with the one or two Mg—X units.

According to some of any of these embodiments, the magnesium complex isa mononuclear complex, featuring one Mg—X unit, and is represented byFormula IIA, and according to some of any of these embodiments, themagnesium complex is a dinuclear complex, featuring two Mg—X units, andis represented by Formula IIB:

wherein:

the dashed line represents a coordinative bond;

M is magnesium;

X is a monoanionic ligand, the monoanionic ligand, as described hereinin any of the respective embodiments and any combination thereof,provided that X is not alkoxy or aryloxy;

B_(A), B_(B) and B_(C) are each independently a bridging moiety of 1 to12 carbon atoms;

R₅₁ and R₅₂ are each independently hydrogen, alkyl, cycloalkyl, aryl oralternatively, one or both of R₅₁ and R₅₂ form together, optionally withone or more carbon atoms in B_(C), a heteroalicyclic or heteroaromatic,5 to 7-membered ring; and

R₅₃ and R₅₄ are each independently hydrogen, alkyl, cycloalkyl, aryl oralternatively, one or both of R₅₃ and R₅₄ form together with one or morecarbon atoms in B_(B), a heteroalicyclic or heteroaromatic, 5 to7-membered ring.

In some of any of the embodiments described herein, X in Formula IIA orIIB is halo or amine, as described herein in any of the respectiveembodiments and any combination thereof.

In some of any of the embodiments described herein for Formula IIA andIIB, B_(A) bridging moiety has a general Formula:—(CRaRb)m-C(R₁₇R₁₈)—C(R₁₉R₂₀)—

wherein:

m is an integer of from 1 to 6, or from 1 to 4, or from 1 to 2;

Ra and Rb are each independently hydrogen, alkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxyl, alkoxy, thiol, thioalkoxy,aryloxy, and amine, wherein when m is other than 1, Ra and Rb in each(CRaRb) unit can be the same or different, and one or both Ra and Rb inone unit can form a 5 to 7-membered alicyclic, heteroalicyclic, aromaticor heteroaromatic ring with one or both Ra and Rb of an adjacent unit;and

R₁₇-R₂₀ are each independently hydrogen, alkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxyl, alkoxy, thiol, thioalkoxy,aryloxy, and amine, or, alternatively, two or more of R₁₇-R₂₀ formtogether a 5 to 7-membered alicyclic, heteroalicyclic, aromatic orheteroaromatic ring.

In some of these embodiments, m is 1.

In some of any of these embodiments, Ra and Rb are each hydrogen.

In some of any of these embodiments, R₁₇-R₂₀ form together a substitutedor unsubstituted, 6-membered, aromatic ring.

In some of any of these embodiments, the aromatic ring is unsubstituted,or is substituted by one or two substituents which are not bulky, asdefined herein, (e.g., lower linear alkyls), and the complex has FormulaIIB.

In some of any of these embodiments, the aromatic ring is substituted byone or more bulky substituents as defined herein (see, e.g., R₄₁ and R₄₂in Formula III hereinunder, and the complex has Formula IIB.

In some of any of the embodiments described herein, the B_(B) bridgingmoiety has a general Formula:—(CRcRd)n-C(R₂₁R₂₂)—

wherein:

n is an integer of from 1 to 6, or from 1 to 4, or from 1 to 2;

Rc and Rd are each independently hydrogen, alkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxyl, alkoxy, thiol, thioalkoxy,aryloxy, and amine, wherein when n is other than 1, Rc and Rd in each(CRcRd) unit being the same or different, and one or both Rc and Rd inone unit optionally forms a 5 to 7-membered alicyclic, heteroalicyclic,aromatic or heteroaromatic ring with one or both Rc and Rd of anadjacent unit; and

R₂₁ and R₂₂ are each independently hydrogen, alkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxyl, alkoxy, thiol, thioalkoxy,aryloxy, and amine, or, alternatively, at least two of R₅₃, R₅₄, R₂₁ andR₂₂ form together a 5 to 7-membered heteroalicyclic or heteroaromaticring.

In some of these embodiments n is 1.

In some of these embodiments, Rc and Rd are each hydrogen.

In some of any of these embodiments, R₅₃, R₅₄, R₂₁ and R₂₂ form togethera substituted or unsubstituted, 6-membered, heteroaromatic ring (e.g., apyrrolidone).

In some of any of the embodiments described herein, the B_(C) bridgingmoiety has a general Formula:—(CRzRw)q-C(R₂₁R₂₂)—

wherein:

q is an integer of from 1 to 6, or from 1 to 4, or from 1 to 2;

Rz and Rw are each independently hydrogen, alkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxyl, alkoxy, thiol, thioalkoxy,aryloxy, and amine, wherein when q is other than 1, Rz and Rw in each(CRzRw) unit being the same or different, and one or both Rz and Rw inone unit optionally forms a 5 to 7-membered alicyclic, heteroalicyclic,aromatic or heteroaromatic ring with one or both Rz and Rw of anadjacent unit; and

R₂₁ and R₂₂ are each independently hydrogen, alkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxyl, alkoxy, thiol, thioalkoxy,aryloxy, and amine, or, alternatively, at least two of R₅₁, R₅₂, R₂₁ andR₂₂ form together a 5 to 7-membered heteroalicyclic or heteroaromaticring.

In some of these embodiments q is 1.

In some of these embodiments, Rz and Rw are each hydrogen.

In some of these embodiments R₅₁, R₅₂, R₂₁ and R₂₂ form together asubstituted or unsubstituted, 6-membered, heteroaromatic ring (e.g., apyrollidine).

Any of the embodiments described herein for the B_(B) bridging moiety inFormula I are contemplated for the B_(B) and B_(C) bridging moieties ofFormula IIA or IIB.

Any of the embodiments described herein for the B_(A) bridging moiety inFormula I are contemplated for the B_(A) bridging moiety of Formula IIAor IIB.

In some of any of the embodiments described herein, the organometalliccomplex is represented by Formula III:

wherein:

R₄₁-R₄₈ and R₅₃-R₅₆ are each independently selected from the groupconsisting of hydrogen, alkyl, cycloalkyl, aryl, halo, alkoxy, aryloxy,trialkylsilyl, heteroalicyclic, heteroaryl, and amine, and all othervariables are as described herein.

In some of these embodiments, at least one of R₄₁-R₄₄ is alkyl.

In some of these embodiments, at least one of R₄₁ and R₄₂ is alkyl.

In some of any of these embodiments, the alkyl is a bulky alkyl asdescribed herein in any of the respective embodiments, and in someembodiments, it is a rigid bulky alkyl, as described herein in any ofthe respective embodiments.

In some of any of these embodiments, each of R₄₅-R₄₈ and R₅₃-R₅₆ ishydrogen.

In some of any of the embodiments described herein, the polymer is ablock copolymer comprising a plurality of units, at least two of theunits independently comprise a plurality of polymerized monomers of acyclic ester, at least one unit of the at least two units comprises aplurality of polymerized monomers of a first cyclic ester, and at leastone another unit of the at least two units comprises a plurality ofpolymerized monomers of a second cyclic ester, the second cyclic esterdiffering from the first cyclic ester by a stereoconfiguration and/or achemical composition, the process comprising:

sequentially contacting a plurality of monomers of the first cyclicester and a plurality of monomers of the second cyclic ester with thecatalyst system comprising an initiator and an organometallic magnesiumcomplex comprising a Mg—X unit and a divergent {ONNN} ligand incoordination with the Mg—X, to thereby sequentially effect a ringopening polymerization of the first cyclic ester and of the secondcyclic ester.

According to an aspect of some embodiments of the present inventionthere is provided an organometallic complex represented by Formula III,as described herein.

In some of these embodiments, X is other than alkoxy or aryloxy, and is,for example, halo (e.g., chloro) or amine; and/or

at least one of R₄₁ and R₄₂ is a bulky rigid alkyl, as defined herein.

According to an aspect of some embodiments of the present inventionthere is provided an organometallic complex represented by Formula IIB,as described herein in any of the respective embodiments.

In some embodiments, these is provided ligand precursor compoundrepresented by Formula IV:

wherein:

m, n and q are each independently an integer of from 1 to 6, or from 1to 4, or from 1 to 2;

Ra and Rb are each independently hydrogen, alkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxyl, alkoxy, thiol, thioalkoxy,aryloxy, and amine, wherein when m is other than 1, Ra and Rb in each(CRaRb) unit can be the same or different, and one or both Ra and Rb inone unit can form a 5 to 7-membered alicyclic, heteroalicyclic, aromaticor heteroaromatic ring with one or both Ra and Rb of an adjacent unit;

Rc and Rd are each independently hydrogen, alkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxyl, alkoxy, thiol, thioalkoxy,aryloxy, and amine, wherein when n is other than 1, Rc and Rd in each(CRcRd) unit being the same or different, and one or both Rc and Rd inone unit optionally forms a 5 to 7-membered alicyclic, heteroalicyclic,aromatic or heteroaromatic ring with one or both Rc and Rd of anadjacent unit;

Rz and Rw are each independently hydrogen, alkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxyl, alkoxy, thiol, thioalkoxy,aryloxy, and amine, wherein when q is other than 1, Rz and Rw in each(CRzRw) unit being the same or different, and one or both Rz and Rw inone unit optionally forms a 5 to 7-membered alicyclic, heteroalicyclic,aromatic or heteroaromatic ring with one or both Rz and Rw of anadjacent unit; and

R₄₁-R₄₈ and R₅₃-R₅₆ are each independently selected from the groupconsisting of hydrogen, alkyl, cycloalkyl, aryl, halo, alkoxy, aryloxy,trialkylsilyl, heteroalicyclic, heteroaryl, and amine, provided that atleast one of R₄₁ and R₄₂ is a bulky rigid alkyl.

All variables of Formula IV are as defined herein in any of therespective embodiments.

As used herein the term “about” refers to ±10% or to ±5%.

The terms “comprises”, “comprising”, “includes”, “including”, “having”and their conjugates mean “including but not limited to”.

The term “consisting of” means “including and limited to”.

The term “consisting essentially of” means that the composition, methodor structure may include additional ingredients, steps and/or parts, butonly if the additional ingredients, steps and/or parts do not materiallyalter the basic and novel characteristics of the claimed composition,method or structure.

As used herein, the singular form “a”, “an” and “the” include pluralreferences unless the context clearly dictates otherwise. For example,the term “a compound” or “at least one compound” may include a pluralityof compounds, including mixtures thereof.

Throughout this application, various embodiments of this invention maybe presented in a range format. It should be understood that thedescription in range format is merely for convenience and brevity andshould not be construed as an inflexible limitation on the scope of theinvention. Accordingly, the description of a range should be consideredto have specifically disclosed all the possible subranges as well asindividual numerical values within that range. For example, descriptionof a range such as from 1 to 6 should be considered to have specificallydisclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numberswithin that range, for example, 1, 2, 3, 4, 5, and 6. This appliesregardless of the breadth of the range.

Whenever a numerical range is indicated herein, it is meant to includeany cited numeral (fractional or integral) within the indicated range.The phrases “ranging/ranges between” a first indicate number and asecond indicate number and “ranging/ranges from” a first indicate number“to” a second indicate number are used herein interchangeably and aremeant to include the first and second indicated numbers and all thefractional and integral numerals therebetween.

As used herein the term “method” refers to manners, means, techniquesand procedures for accomplishing a given task including, but not limitedto, those manners, means, techniques and procedures either known to, orreadily developed from known manners, means, techniques and proceduresby practitioners of the chemical, pharmacological, biological,biochemical and medical arts.

Herein throughout, the phrase “linking moiety” or “linking group”describes a group that connects two or more moieties or groups in acompound. A linking moiety is typically derived from a bi- ortri-functional compound, and can be regarded as a bi- or tri-radicalmoiety, which is connected to two or three other moieties, via two orthree atoms thereof, respectively.

Exemplary linking moieties include a hydrocarbon moiety or chain,optionally interrupted by one or more heteroatoms, as defined herein,and/or any of the chemical groups listed below, when defined as linkinggroups.

When a chemical group is referred to herein as “end group” it is to beinterpreted as a substituent, which is connected to another group viaone atom thereof.

Herein throughout, the term “hydrocarbon” collectively describes achemical group composed mainly of carbon and hydrogen atoms. Ahydrocarbon can be comprised of alkyl, alkene, alkyne, aryl, and/orcycloalkyl, each can be substituted or unsubstituted, and can beinterrupted by one or more heteroatoms. The number of carbon atoms canrange from 2 to 20, and is preferably lower, e.g., from 1 to 10, or from1 to 6, or from 1 to 4. A hydrocarbon can be a linking group or an endgroup.

Bisphenol A is An example of a hydrocarbon comprised of 2 aryl groupsand one alkyl group.

As used herein, the term “amine” describes both a —NR′R″ group and a—NR′ group, wherein R′ and R″ are each independently hydrogen, alkyl,cycloalkyl, aryl, alkaryl, heteroaryl, heteroalicylic, as these termsare defined hereinbelow.

The amine group can therefore be a primary amine, where both R′ and R″are hydrogen, a secondary amine, where R′ is hydrogen and R″ is alkyl,cycloalkyl or aryl, or a tertiary amine, where each of R′ and R″ isindependently alkyl, cycloalkyl or aryl.

Alternatively, R′ and R″ can each independently be hydroxyalkyl,trihaloalkyl, alkenyl, alkynyl, amine, halide, sulfonate, sulfoxide,phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy,thioaryloxy, cyano, nitro, azo, sulfonamide, carbonyl, C-carboxylate,O-carboxylate, N-thiocarbamate, O-thiocarbamate, urea, thiourea,N-carbamate, O-carbamate, C-amide, N-amide, silyl, guanyl, guanidine andhydrazine.

The term “amine” is used herein to describe a —NR′R″ group in caseswhere the amine is an end group, as defined hereinunder, and is usedherein to describe a —NR′ group in cases where the amine is a linkinggroup or is or part of a linking moiety.

The term “alkyl” describes a saturated aliphatic hydrocarbon includingstraight chain and branched chain groups. Preferably, the alkyl grouphas 1 to 20 carbon atoms. Whenever a numerical range; e.g., “1-20”, isstated herein, it implies that the group, in this case the alkyl group,may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up toand including 20 carbon atoms. More preferably, the alkyl is a mediumsize alkyl having 1 to 10 carbon atoms. Most preferably, unlessotherwise indicated, the alkyl is a lower alkyl having 1 to 6, or 1 to 4carbon atoms (C(1-4) alkyl). The alkyl group may be substituted orunsubstituted. Substituted alkyl may have one or more substituents,whereby each substituent group can independently be, for example,hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide,phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy,thioaryloxy, cyano, nitro, azo, sulfonamide, C-carboxylate,O-carboxylate, N-thiocarbamate, O-thiocarbamate, urea, thiourea,N-carbamate, O-carbamate, C-amide, N-amide, silyl, guanyl, guanidine andhydrazine.

The alkyl group can be an end group, as this phrase is definedhereinabove, wherein it is attached to a single adjacent atom, or alinking group, as this phrase is defined hereinabove, which connects twoor more moieties via at least two carbons in its chain. When the alkylis a linking group, it is also referred to herein as “alkylene” or“alkylene chain”.

Alkene (or alkenyl) and Alkyne (or alkynyl), as used herein, are analkyl, as defined herein, which contains one or more double bond ortriple bond, respectively.

The term “cycloalkyl” describes an all-carbon monocyclic ring or fusedrings (i.e., rings which share an adjacent pair of carbon atoms) groupwhere one or more of the rings does not have a completely conjugatedpi-electron system. Examples include, without limitation, cyclohexane,adamantine, norbornyl, isobornyl, and the like. The cycloalkyl group maybe substituted or unsubstituted. Substituted cycloalkyl may have one ormore substituents, whereby each substituent group can independently be,for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, alkaryl, heteroalicyclic, amine, halide, sulfonate,sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy,thioalkoxy, thioaryloxy, cyano, nitro, azo, sulfonamide, C-carboxylate,O-carboxylate, N-thiocarbamate, O-thiocarbamate, urea, thiourea,N-carbamate, O-carbamate, C-amide, N-amide, silyl, guanyl, guanidine andhydrazine. The cycloalkyl group can be an end group, as this phrase isdefined hereinabove, wherein it is attached to a single adjacent atom,or a linking group, as this phrase is defined hereinabove, connectingtwo or more moieties at two or more positions thereof.

The term “heteroalicyclic” describes a monocyclic or fused ring grouphaving in the ring(s) one or more atoms such as nitrogen, oxygen andsulfur. The rings may also have one or more double bonds. However, therings do not have a completely conjugated pi-electron system.Representative examples are piperidine, piperazine, tetrahydrofuran,tetrahydropyrane, morpholine, oxalidine, and the like. Theheteroalicyclic may be substituted or unsubstituted. Substitutedheteroalicyclic may have one or more substituents, whereby eachsubstituent group can independently be, for example, hydroxyalkyl,trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkaryl,heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate,hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano,nitro, azo, sulfonamide, C-carboxylate, O-carboxylate, N-thiocarbamate,O-thiocarbamate, urea, thiourea, O-carbamate, N-carbamate, C-amide,N-amide, silyl, guanyl, guanidine and hydrazine. The heteroalicyclicgroup can be an end group, as this phrase is defined hereinabove, whereit is attached to a single adjacent atom, or a linking group, as thisphrase is defined hereinabove, connecting two or more moieties at two ormore positions thereof.

The term “aryl” describes an all-carbon monocyclic or fused-ringpolycyclic (i.e., rings which share adjacent pairs of carbon atoms)groups having a completely conjugated pi-electron system. The aryl groupmay be substituted or unsubstituted. Substituted aryl may have one ormore substituents, whereby each substituent group can independently be,for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, alkaryl, heteroalicyclic, amine, halide, sulfonate,sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy,thioalkoxy, thioaryloxy, cyano, nitro, azo, sulfonamide, C-carboxylate,O-carboxylate, N-thiocarbamate, O-thiocarbamate, urea, thiourea,N-carbamate, O-carbamate, C-amide, N-amide, silyl, guanyl, guanidine andhydrazine. The aryl group can be an end group, as this term is definedhereinabove, wherein it is attached to a single adjacent atom, or alinking group, as this term is defined hereinabove, connecting two ormore moieties at two or more positions thereof.

The term “heteroaryl” describes a monocyclic or fused ring (i.e., ringswhich share an adjacent pair of atoms) group having in the ring(s) oneor more atoms, such as, for example, nitrogen, oxygen and sulfur and, inaddition, having a completely conjugated pi-electron system. Examples,without limitation, of heteroaryl groups include pyrrole, furan,thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine,quinoline, isoquinoline and purine. The heteroaryl group may besubstituted or unsubstituted. Substituted heteroaryl may have one ormore substituents, whereby each substituent group can independently be,for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, alkaryl, heteroalicyclic, amine, halide, sulfonate,sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy,thioalkoxy, thioaryloxy, cyano, nitro, azo, sulfonamide, C-carboxylate,O-carboxylate, N-thiocarbamate, O-thiocarbamate, urea, thiourea,O-carbamate, N-carbamate, C-amide, N-amide, silyl, guanyl, guanidine andhydrazine. The heteroaryl group can be an end group, as this phrase isdefined hereinabove, where it is attached to a single adjacent atom, ora linking group, as this phrase is defined hereinabove, connecting twoor more moieties at two or more positions thereof. Representativeexamples are pyridine, pyrrole, pyrrolidone, oxazole, indole, purine andthe like.

The term “piperazine” refers to a group or a

or a

group, where R′ and R″ are as defined hereinabove.

The term “piperidine” refers to a group

or a

group, with R′ as defined herein.

The term “pyrrolidine” refers to a

group or a

group, with R′ as defined herein.

The term “pyridine” refers to a

group.

The term pyrrole refers to a

group or a

group, with R′ as defined herein.

The term “morpholine” refers to a

group, and encompasses also thiomorpholine.

The term “thiomorpholine” refers to a

group.

The term “hexahydroazepine” refers to a

group.

The term “alkaryl” describes an alkyl, as defined herein, which issubstituted by one or more aryl or heteroaryl groups, as defined herein.An example of alkaryl is benzyl.

The term “halide”, “halogen” and “halo” describe fluorine, chlorine,bromine or iodine.

The term “haloalkyl” describes an alkyl group as defined above, furthersubstituted by one or more halide.

The term “sulfate” describes a —O—S(═O)₂—OR′ end group, as this term isdefined hereinabove, or an —O—S(═O)₂—O— linking group, as these phrasesare defined hereinabove, where R′ is as defined hereinabove.

The term “thiosulfate” describes a —O—S(═S)(═O)—OR′ end group or a—O—S(═S)(═O)—O— linking group, as these phrases are defined hereinabove,where R′ is as defined hereinabove.

The term “sulfite” describes an —O—S(═O)—O—R′ end group or a —O—S(═O)—O—group linking group, as these phrases are defined hereinabove, where R′is as defined hereinabove.

The term “thiosulfite” describes a —O—S(═S)—O—R′ end group or an—O—S(═S)—O— group linking group, as these phrases are definedhereinabove, where R′ is as defined hereinabove.

The term “sulfinate” describes a —S(═O)—OR′ end group or an —S(═O)—O—group linking group, as these phrases are defined hereinabove, where R′is as defined hereinabove.

The term “sulfoxide” or “sulfinyl” describes a —S(═O)R′ end group or an—S(═O)— linking group, as these phrases are defined hereinabove, whereR′ is as defined hereinabove.

The term “sulfonate” describes a —S(═O)₂—R′ end group or an —S(═O)₂—linking group, as these phrases are defined hereinabove, where R′ is asdefined herein.

The term “S-sulfonamide” describes a —S(═O)₂—NR′R″ end group or a—S(═O)₂—NR′— linking group, as these phrases are defined hereinabove,with R′ and R″ as defined herein.

The term “N-sulfonamide” describes an R'S(═O)₂—NR″— end group or a—S(═O)₂—NR′— linking group, as these phrases are defined hereinabove,where R′ and R″ are as defined herein.

The term “disulfide” refers to a —S—SR′ end group or a —S—S— linkinggroup, as these phrases are defined hereinabove, where R′ is as definedherein.

The term “oxo” as used herein, describes a (═O) group, wherein an oxygenatom is linked by a double bond to the atom (e.g., carbon atom) at theindicated position.

The term “thiooxo” as used herein, describes a (═S) group, wherein asulfur atom is linked by a double bond to the atom (e.g., carbon atom)at the indicated position.

The term “oxime” describes a ═N—OH end group or a ═N—O— linking group,as these phrases are defined hereinabove.

The term “hydroxyl” describes a —OH group.

The term “alkoxy” describes both an —O-alkyl and an —O-cycloalkyl group,as defined herein.

The term “aryloxy” describes both an —O-aryl and an —O-heteroaryl group,as defined herein.

The term “thiohydroxy” describes a —SH group.

The term “thioalkoxy” describes both a —S-alkyl group, and a—S-cycloalkyl group, as defined herein.

The term “thioaryloxy” describes both a —S-aryl and a —S-heteroarylgroup, as defined herein.

The “hydroxyalkyl” is also referred to herein as “alcohol”, anddescribes an alkyl, as defined herein, substituted by a hydroxy group.

The term “cyano” describes a —C≡N group.

The term “cyanurate” describes a

end group or

linking group, with R′ and R″ as defined herein.

The term “isocyanurate” describes a R

end group or a

linking group, with R′ and R″ as defined herein.

The term “thiocyanurate” describes a

end group or

linking group, with R′ and R″ as defined herein.

The term “isocyanate” describes an —N═C═O group.

The term “isothiocyanate” describes an —N═C═S group.

The term “nitro” describes an —NO₂ group.

The term “acyl halide” describes a —(C═O)R″″ group wherein R″″ ishalide, as defined hereinabove.

The term “azo” or “diazo” describes an —N═NR′ end group or an —N═N—linking group, as these phrases are defined hereinabove, with R′ asdefined hereinabove.

The term “peroxo” describes an —O—OR′ end group or an —O—O— linkinggroup, as these phrases are defined hereinabove, with R′ as definedhereinabove.

The term “carboxylate” as used herein encompasses C-carboxylate andO-carboxylate.

The term “C-carboxylate” describes a —C(═O)—OR′ end group or a —C(═O)—O—linking group, as these phrases are defined hereinabove, where R′ is asdefined herein.

The term “O-carboxylate” describes a —OC(═O)R′ end group or a —OC(═O)—linking group, as these phrases are defined hereinabove, where R′ is asdefined herein.

A carboxylate can be linear or cyclic. When cyclic, R′ and the carbonatom are linked together to form a ring, in C-carboxylate, and thisgroup is also referred to as lactone. Alternatively, R′ and O are linkedtogether to form a ring in O-carboxylate. Cyclic carboxylates canfunction as a linking group, for example, when an atom in the formedring is linked to another group.

The term “thiocarboxylate” as used herein encompasses C-thiocarboxylateand O-thiocarboxylate.

The term “C-thiocarboxylate” describes a —C(═S)—OR′ end group or a—C(═S)—O— linking group, as these phrases are defined hereinabove, whereR′ is as defined herein.

The term “O-thiocarboxylate” describes a —OC(═S)R′ end group or a—OC(═S)— linking group, as these phrases are defined hereinabove, whereR′ is as defined herein.

A thiocarboxylate can be linear or cyclic. When cyclic, R′ and thecarbon atom are linked together to form a ring, in C-thiocarboxylate,and this group is also referred to as thiolactone. Alternatively, R′ andO are linked together to form a ring in O-thiocarboxylate. Cyclicthiocarboxylates can function as a linking group, for example, when anatom in the formed ring is linked to another group.

The term “carbamate” as used herein encompasses N-carbamate andO-carbamate.

The term “N-carbamate” describes an R″OC(═O)—NR′— end group or a—OC(═O)—NR′— linking group, as these phrases are defined hereinabove,with R′ and R″ as defined herein.

The term “O-carbamate” describes an —OC(═O)—NR′R″ end group or an—OC(═O)—NR′— linking group, as these phrases are defined hereinabove,with R′ and R″ as defined herein.

A carbamate can be linear or cyclic. When cyclic, R′ and the carbon atomare linked together to form a ring, in O-carbamate. Alternatively, R′and O are linked together to form a ring in N-carbamate. Cycliccarbamates can function as a linking group, for example, when an atom inthe formed ring is linked to another group.

The term “carbamate” as used herein encompasses N-carbamate andO-carbamate.

The term “thiocarbamate” as used herein encompasses N-thiocarbamate andO-thiocarbamate.

The term “O-thiocarbamate” describes a —OC(═S)—NR′R″ end group or a—OC(═S)—NR′— linking group, as these phrases are defined hereinabove,with R′ and R″ as defined herein.

The term “N-thiocarbamate” describes an R″OC(═S)NR′— end group or a—OC(═S)NR′— linking group, as these phrases are defined hereinabove,with R′ and R″ as defined herein.

Thiocarbamates can be linear or cyclic, as described herein forcarbamates.

The term “dithiocarbamate” as used herein encompasses S-dithiocarbamateand N-dithiocarbamate.

The term “S-dithiocarbamate” describes a —SC(═S)—NR′R″ end group or a—SC(═S)NR′— linking group, as these phrases are defined hereinabove,with R′ and R″ as defined herein.

The term “N-dithiocarbamate” describes an R″SC(═S)NR′— end group or a—SC(═S)NR′— linking group, as these phrases are defined hereinabove,with R′ and R″ as defined herein.

The term “urea”, which is also referred to herein as “ureido”, describesa —NR′C(═O)—NR″R′″ end group or a —NR′C(═O)—NR″— linking group, as thesephrases are defined hereinabove, where R′ and R″ are as defined hereinand R′″ is as defined herein for R′ and R″.

The term “thiourea”, which is also referred to herein as “thioureido”,describes a —NR′—C(═S)—NR″R′″ end group or a —NR′—C(═S)—NR″— linkinggroup, with R′, R″ and R′″ as defined herein.

The term “amide” as used herein encompasses C-amide and N-amide.

The term “C-amide” describes a —C(═O)—NR′R″ end group or a —C(═O)—NR′—linking group, as these phrases are defined hereinabove, where R′ and R″are as defined herein.

The term “N-amide” describes a R′C(═O)—NR″— end group or a R′C(═O)—N—linking group, as these phrases are defined hereinabove, where R′ and R″are as defined herein.

An amide can be linear or cyclic. When cyclic, R′ and the carbon atomare linked together to form a ring, in C-amide, and this group is alsoreferred to as lactam. Cyclic amides can function as a linking group,for example, when an atom in the formed ring is linked to another group.

The term “guanyl” describes a R′R″NC(═N)— end group or a —R′NC(═N)—linking group, as these phrases are defined hereinabove, where R′ and R″are as defined herein.

The term “guanidine” describes a —R′NC(═N)—NR″R′″ end group or a—R′NC(═N)— NR″— linking group, as these phrases are defined hereinabove,where R′, R″ and R′″ are as defined herein.

The term “hydrazine” describes a —NR′—NR″R′″ end group or a —NR′— NR″—linking group, as these phrases are defined hereinabove, with R′, R″,and R′″ as defined herein.

As used herein, the term “hydrazide” describes a —C(═O)—NR′—NR″R′″ endgroup or a —C(═O)—NR′—NR″— linking group, as these phrases are definedhereinabove, where R′, R″ and R′″ are as defined herein.

As used herein, the term “thiohydrazide” describes a —C(═S)—NR′—NR″R′″end group or a —C(═S)—NR′—NR″— linking group, as these phrases aredefined hereinabove, where R′, R″ and R′″ are as defined herein.

As used herein, the term “alkylene glycol” describes a—O—[(CR′R″)_(z)—O]_(y)—R′″ end group or a —O—[(CR′R″)_(z)—O]_(y)—linking group, with R′, R″ and R′″ being as defined herein, and with zbeing an integer of from 1 to 10, preferably, 2-6, more preferably 2 or3, and y being an integer of 1 or more. Preferably R′ and R″ are bothhydrogen. When z is 2 and y is 1, this group is ethylene glycol. When zis 3 and y is 1, this group is propylene glycol.

When y is greater than 4, the alkylene glycol is referred to herein aspoly(alkylene glycol). In some embodiments of the present invention, apoly(alkylene glycol) group or moiety can have from 10 to 200 repeatingalkylene glycol units, such that z is 10 to 200, preferably 10-100, morepreferably 10-50.

The term “silyl” describes a —SiR′R″R′″ end group or a —SiR′R″— linkinggroup, as these phrases are defined hereinabove, whereby each of R′, R″and R′″ are as defined herein.

The term “siloxy” describes a —Si(OR′)R″R′″ end group or a —Si(OR′)R″—linking group, as these phrases are defined hereinabove, whereby each ofR′, R″ and R′″ are as defined herein.

The term “silaza” describes a —Si(NR′R″)R′″ end group or a —Si(NR′R″)—linking group, as these phrases are defined hereinabove, whereby each ofR′, R″ and R′″ is as defined herein.

The term “silicate” describes a —O—Si(OR′)(OR″)(OR′″) end group or a—O—Si(OR′)(OR″)— linking group, as these phrases are definedhereinabove, with R′, R″ and R′″ as defined herein.

As used herein, the term “epoxide” describes a

end group or a

linking group, as these phrases are defined hereinabove, where R′, R″and R′″ are as defined herein.

As used herein, the term “methyleneamine” describes an—NR′—CH₂—CH═CR″R′″ end group or a —NR′—CH₂—CH═CR″— linking group, asthese phrases are defined hereinabove, where R′, R″ and R′″ are asdefined herein.

The term “phosphonate” describes a —P(═O)(OR′)(OR″) end group or a—P(═O)(OR′)(O)— linking group, as these phrases are defined hereinabove,with R′ and R″ as defined herein.

The term “thiophosphonate” describes a —P(═S)(OR′)(OR″) end group or a—P(═S)(OR′)(O)— linking group, as these phrases are defined hereinabove,with R′ and R″ as defined herein.

The term “phosphinyl” describes a —PR′R″ end group or a —PR′— linkinggroup, as these phrases are defined hereinabove, with R′ and R″ asdefined hereinabove.

The term “phosphine oxide” describes a —P(═O)(R′)(R″) end group or a—P(═O)(R′)— linking group, as these phrases are defined hereinabove,with R′ and R″ as defined herein.

The term “phosphine sulfide” describes a —P(═S)(R′)(R″) end group or a—P(═S)(R′)— linking group, as these phrases are defined hereinabove,with R′ and R″ as defined herein.

The term “phosphite” describes an —O—PR′(═O)(OR″) end group or an—O—PH(═O)(O)— linking group, as these phrases are defined hereinabove,with R′ and R″ as defined herein.

The term “carbonyl” or “carbonate” as used herein, describes a —C(═O)—R′end group or a —C(═O)— linking group, as these phrases are definedhereinabove, with R′ as defined herein. This term encompasses ketonesand aldehydes.

The term “thiocarbonyl” as used herein, describes a —C(═S)—R′ end groupor a —C(═S)— linking group, as these phrases are defined hereinabove,with R′ as defined herein.

The term “oxime” describes a ═N—OH end group or a ═N—O— linking group,as these phrases are defined hereinabove.

The term “cyclic ring” encompasses a cycloalkyl, a heteroalicyclic, anaryl (an aromatic ring) and a heteroaryl (a heteroaromatic ring).

Other chemical groups are to be regarded according to the commondefinition thereof in the art and/or in line of the definitions providedherein.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination or as suitable in any other describedembodiment of the invention. Certain features described in the contextof various embodiments are not to be considered essential features ofthose embodiments, unless the embodiment is inoperative without thoseelements.

Various embodiments and aspects of the present invention as delineatedhereinabove and as claimed in the claims section below find experimentalsupport in the following examples.

EXAMPLES

Reference is now made to the following examples, which together with theabove descriptions illustrate some embodiments of the invention in a nonlimiting fashion.

Materials and Methods

All reactions with air- and/or water sensitive compounds were carriedout using standard Schlenk or glovebox techniques under dry N₂atmosphere. Pentane was washed with HNO₃/H₂SO₄ prior to distillationfrom Na/benzophenone/tetraglyme. Toluene was refluxed over Na anddistilled. Dichloromethane was refluxed over CaH₂ and distilled. Benzylmagnesium chloride solution, anhydrous benzyl alcohol,1,4-benzenedimethanol and salicylaldehyde were purchased from Aldrichand used as received. Bis(2-pyridylmethyl)amine was purchased from TCIand used as received. Sodium triacetoxyborohydride was purchased fromStrem and used as received. L-lactide and D-lactide were given as giftfrom Corbion (Purac), and were purified by crystallization from drytoluene and sublimation. F-Caprolactone was purchased from Merck, andwas refluxed over CaH₂ and distilled prior to use.

The ligand precursor Lig¹H was synthesized following a previouslypublished procedure. See, for example, Rosen et al., Chem. Eur. J. 2016,22, 11533-11536.

The ligand precursors Lig²⁻⁶H were synthesized following a previouslypublished procedure. See, for example, Rosen et al., Chem. Sci. DOI:10.1039/C7SC01514C.

The magnesium precursor Mg(HMDS)₂ was synthesized following a previouslypublished procedure. See, for example, Allan et al., Chem. Commun. 1999,1325-1326.

Deuterated solvents were purchased from Cambridge Isotope Laboratories,Inc., degassed, and dried over activated 4 A molecular sieves prior touse.

The NMR spectra were recorded on a Bruker Avance 500 spectrometer at 25°C., unless otherwise stated. Chemical shifts (6) are listed as parts permillion and coupling constants (J) in Hertz. ¹H NMR spectra arereferenced using the residual solvent peak at δ=5.32 for CD₂Cl₂. ¹³C NMRspectra are referenced using the residual solvent peak at δ=53.84 forCD₂Cl₂.

The molecular weights (Mn and Mw) and the molecular mass distributions(Mw/Mn) of the PLA samples were measured by gel permeationchromatography (GPC) at 40° C., using THF as solvent, flow rate ofeluent of 1 mL/min, and narrow Mw polystyrene standards as reference.The measurements were performed on a Jasco system equipped with an RI1530 detector. A correction factor of 0.58 was employed for themolecular weight of PLA relative to polystyrene. Insoluble PLA sampleswere measured using chloroform as solvent at 30° C. with flow rate ofeluent of 0.8 mL/min.

High resolution MS was obtained on SYNAPT (Waters Inc.) spectrometer.Ionization methods: APPI (positive or negative). X-ray diffractionmeasurements were performed on an ApexDuo (Bruker-AXS) diffractometersystem, using Mo Kα (λ=0.7107 Å) radiation. The analyzed crystals wereembedded within a drop of viscous oil and freeze-cooled to ca. 110 K.

MALDI-TOF analysis was carried out on a Bruker autoflex massspectrometer. The polymer samples were dissolved in THF at aconcentration of 10 mg/ml. The matrix used was either HABA(2-(4-hydroxyphenylazo) benzoic acid) or α-CCA(α-cyano-4-hydroxycinanamic acid) with sodium trifluoroacetate ascationization agent. The final matrix solution was prepared in thevolume ratio of 10:1:3 of solutions of matrix, salt and polymer sample,respectively. A portion of this mixture was then placed on the MALDIplate and allowed to dry in air. The spectra were recorded in positivelinear mode or positive reflectron mode.

Differential scanning calorimetry analysis was performed on a TA 2920DSC (TA Instruments) according to the following program: Ramp 10.00°C./min to 200.00° C.; Equilibrate at 195.00° C.; Isothermal for 2 min;Ramp 10.00° C./min to 50.00° C.; Equilibrate at 50.00° C.; Ramp 10.00°C./min to 200.00° C. Melting transitions were determined on the secondheating run with a nitrogen purge at a flow rate of 40 mL s−1.

The instrument was calibrated for temperature and enthalpy by highpurity indium (156.60° C., 28.45 J g−1) standard.

Example 1 Synthesis of Magnesium Complexes of Sequential {ONNN} LigandsSynthesis of (R,R)-Lig¹Mg—Cl

Scheme 2 below presents the preferred synthetic pathway for preparing anexemplary Mg complex according to some embodiments of the presentinvention.

To a stirred solution of (R,R)-Lig¹H (110 mg, 0.24 mmol) in toluene (1mL), was added a solution of BnMgCl (0.24 mL, 0.24 mmol, 1M diethylether solution) drop-wise. The resulting mixture was stirred at roomtemperature for 1 hour until a precipitation appeared. The solvent wasremoved under vacuum and the residue was washed with pentane to give ayellow solid in 81% yield.

¹H NMR analysis revealed that the obtained {ONNN}Mg—Cl complex hadformed as a single rigid stereoisomer, and X-ray diffractionmeasurements revealed a pentacoordinate mononuclear magnesium complexsimilar to the corresponding zinc complex, as shown in FIG. 2 .

¹H NMR (CD₂Cl₂, 500 MHz): δ 8.94 (d, 1H, J=4.91 Hz, ArH), 7.87 (td, 1H,J=1.57 Hz, J=7.73 Hz, ArH), 7.48 (dd, 1H, J=5.21 Hz, 7.66 Hz, ArH), 7.30(d, 1H, J=7.68 Hz, ArH), 7.18 (d, 1H, J=2.59 Hz, ArH), 6.79 (d, 1H,J=2.65 Hz, ArH), 4.20 (d, 1H, J=14.45 Hz, CH₂), 3.84 (d, 1H, J=11.46 Hz,CH₂), 3.70 (d, 1H, J=14.52 Hz, CH₂), 3.46 (d, 1H, 11.44 Hz, CH₂),3.22-3.16 (m, 2H, CH₂), 2.93-2.87 (m, 1H, CH₂), 2.80 (qd, 1H, J=2.49 Hz,CH), 2.67 (dt, 1H, J=6.63 Hz, CH₂), 2.54-2.50 (m, 1H, CH₂), 2.12-2.04(m, 3H, CH₂), 1.96-1.91 (m, 2H, CH₂), 1.86-1.84 (m, 1H, CH₂), 1.74-1.68(m, 1H, CH₂), 1.59-1.52 (m, 1H, CH₂), 1.47 (s, 9H, C(CH₃)₃), 1.26 (s,9H, C(CH₃)₃).

¹³C NMR (CD₂Cl₂, 125 MHz): δ 163.46 (C), 156.33 (C), 149.34 (CH), 139.60(CH), 137.20 (C), 134.37 (C), 126.08 (CH), 124.54 (CH), 123.94 (CH),123.81 (CH), 69.98 (CH₂), 67.36 (CH), 63.28 (CH), 59.01 (CH₂), 50.91(CH₂), 35.47 (C), 34.06 (C), 32.06 (CH₃), 29.78 (CH₃), 28.03 (CH₂),26.54 (CH₂), 23.95 (CH₂), 20.51 (CH₂).

HRMS (APPI⁺): Calc for C₂₉H₄₂ClMgN₃O: 507.2867, found: 507.2874 (M⁺).

Crystal Data for Complex [(R,R)-Lig¹Mg—Cl.CH₂Cl₂]. C₂₉H₄₂CN₃OMg, CH₂Cl₂;M=593.34; orthorhombic; space group P 21 21 21; a=7.9066(5) Å,b=17.5510(13) Å, c=22.4279(18) Å, V=3112.3(4) Å3; T=110(2) K; Z=4;Dc=1.266 g cm−3; μ(Mo Kα)=0.342 mm−1; R1=0.0733 and wR2=0.1718 for 4786reflections with I>2σ (I); R1=0.0634 and wR2=0.1638 for all 4196 uniquereflections.

Synthesis of (R,R)-Lig¹Mg-HMDS

To a stirred solution of Mg(HMDS)₂ (50 mg, 0.14 mmol) in toluene (1 mL),was added a solution of (R,R)-Lig¹H (65 mg, 0.14 mmol) in toluene (1 mL)drop-wise. The resulting mixture was stirred at room temperature for 4hours. The solvent was hereafter removed under vacuum and the residuewas washed with pentane to give an off-white solid in 85% yield

¹H NMR spectroscopy analysis demonstrated that {ONNN}Mg-HMDS had formedas a single rigid stereoisomer of C₁-symmetry, and X-ray diffractionmeasurements revealed a pentacoordinate mononuclear magnesium complexadopting an almost ideal square pyramidal geometry (L=0.06) with thephenolate oxygen at the apical position, as shown in FIG. 3 .

¹H NMR (C₆D₆, 500 MHz): δ 9.17 (d, 1H, J=4.9 Hz, ArH), 7.50 (d, 1H,J=2.6 Hz, ArH), 6.90 (d, 1H, J=2.6 Hz, ArH), 6.86 (dt, 1H, J=7.7 Hz,J=1.7 Hz, ArH), 6.65 (dd, 1H, J=7.7 Hz, J=4.8 Hz, ArH), 6.19 (d, 1H,J=7.7 Hz, ArH), 4.58 (d, 1H, J=12.2 Hz, CH₂), 3.51-3.45 (m, 1H, CH),3.31 (d, 1H, J=15.4 Hz, CH₂), 2.99 (d, 1H, J=12.2 Hz, CH₂), 2.96-2.95(m, 1H, CH), 2.78-2.73 (m, 1H, CH₂), 2.73 (d, 1H, J=15.4 Hz, CH₂),2.30-2.24 (m, 2H, CH₂), 1.82-1.69 (m, 4H, CH₂), 1.56 (s, 9H, C(CH₃)₃),1.44 (s, 9H, C(CH₃)₃), 1.17-1.15 (m, 2H, CH₂), 0.97-0.95 (m, 3H, CH₂),0.76 (s, 9H, Si(CH₃)₃), 0.14 (s, 9H, Si(CH₃)₃). ¹³C NMR (C₆D₆, 125 MHz):δ 165.09 (C), 155.94 (C), 150.64 (CH), 138.44 (CH), 137.20 (C), 132.99(C), 126.56 (CH), 124.12 (CH), 123.36 (CH), 123.16 (C), 122.23(CH),69.40 (CH), 61.85 (CH), 61.76 (CH₂), 59.26 (CH₂), 55.38 (CH₂), 51.34(CH₂), 35.53 (C), 34.08 (C), 32.44 (CH₃), 30.23 (CH₃), 26.32 (CH₂),25.75 (CH₂), 22.82 (CH₂), 19.13 (CH₂), 7.71 (CH₃), 7.05 (CH₃). HRMS(APPI⁺): Calc for C₃₅H₆₀MgN₄OSi₂: 632.4156, found: 472.3162 [M-HMDS]⁺.

Crystal Data for Complex [(R,R)-LigMg-HMDS]. C₃₅H₆₀MgN₄OSi₂; M=633.36;orthorhombic; space group P 2ac 2ab; a=11.4994(6) Å, b=16.5576(7) Å,c=19.7586(8), V=3762.1(3) Å3; T=110(2) K; Z=4; Dc=1.118 g cm⁻³; μ(MoKα)=0.142 mm⁻¹; R1=0.0455 and wR2=0.0833 for 6263 reflections withI>2σ (I); R1=0.0380 and wR2=0.0802 for all 5605 unique reflections.

Example 2 Homo-Polymerization and Block-Polymerization of LactidesEmploying an Exemplary Sequential {ONNN}Mg—Cl Complex

General Homo-Polymerization Procedure:

To a solution of the catalyst (0.01 mmol) in dichloromethane (5 mL),benzyl alcohol (0.01 mmol) was added, and the reaction mixture wasstirred at room temperature for 2 minutes. Then, L-lactide (432 mg, 3mmol) was added, and the reaction was stirred at room temperature. Afterthe desired time, the reaction was terminated by exposing to air and thevolatiles were removed under vacuum.

General Block-Polymerization Procedure: To a solution of the catalyst(0.01 mmol) in dichloromethane (5 mL), benzyl alcohol (2 molequivalents) was added and the reaction mixture was stirred at roomtemperature for 2 minutes. Then, D-Lactide and L-Lactide weresequentially added, each separately, maintaining the necessary delay(5-20 minutes) between each addition. The reaction was terminated byexposing to air and the volatiles were removed under vacuum. Thetacticity of the PLA samples was determined by the homonuclear-decoupled¹H NMR spectrometry (500 MHz, CDCl₃) as previously described in Stopperet al. Macromolecules 45, 698 (2012); Thakur et al. Macromolecules 30,2422 (1997); and Chamberlain et al. J. Am. Chem. Soc. 123, 3229 (2001).

Polymerization Results:

Tables 1 and 2 present the data obtained for homo-polymerization of L-LA(Table 1) and block co-polymerization of L-LA and D-LA (Table 2),employing (R,R)-Lig¹Mg—Cl, in dichloromethane at room temperature.

TABLE 1 Conver- [I]/[LA]/[BnOH] Time sion^(a) M_(n calc) M_(n) PDI 1.  1/0/300 <15 sec >0.99 43200 106600 1.28 2.   1/1/300 1 min >0.99 4320044340 1.04 3. 0.5/1/300 1 min >0.99 43200 41360 1.05 4. 0.5/2/300 1min >0.99 21600 23420 1.05 5. 0.5/1/1000 3 min >0.99 144000 137560 1.066. 0.5/1/2150 5 min >0.99 309600 266000 1.07 ^(a)Determined by 1H-NMRspectroscopy (500 MHz).

TABLE 2 Interval Type Composition (minutes) M_(n) PDI 1. Di Block150L-150D 5 47000 1.04 2. Di Block 150D-150L 5 53000 1.06 3. Di Block300D-300L 10  90000^(b) 1.13 4. Di Block 400L-400D 15 126400^(b) 1.07 5.Di Block 400D-400L 15 128700^(b) 1.08 6. Di Block 500L-500D 15177000^(b) 1.11 7. Tri Block 100L-100D-100L 5 45500 1.06 8. Tri Block100L-200D-100L 5 50000 1.06 9. Tri Block 150L-50D-150L 5 54200 1.07 10.Tri Block 200L-200D-200L 10 81500 1.12 11. Tri Block 200D-200L-200D 1069000 1.13 12. Tri Block 150L-15D-150L 5 40500 1.05 13. Tri Block300L-15D-300L 5-10 87600 1.14 14. Tetra Block 50L-50D-50L-50D 5 254001.04 15. Tetra Block 100L-100D-100L- 5 64300 1.12 100D 16. Tetra Block200L-200D-200L- 5-20 122910^(b) 1.13 200D 17. Tetra Block 200L-33D-200L-5-10 70650 1.14 33D 18. Tetra Block 200L-32D-32L- 5-10 72690 1.31 200D19. Tetra Block 100L-250D-50L- 5-15 75040 1.27 150D 20. Penta Block100L-100D-100L- 5-15 61000 1.12 100D-100L-100D 21. Hexa Block50L-50D-50L-50D- 5-10 34000 1.10 50L-50D-50L 22. Hexa Block100L-b-100D-b- 72820 1.16 100L-b-100D-b- 100L-b-100D 23. Octa Block50L-b-50D-b-50L-b- 50984 1.12 50D-b-50L-b-50D-b- 50L-b-50D-b-50L ^(b)GPCmeasurements were performed with CHCl₃ as eluent at 30° C.

Homonuclear-decoupled ¹H NMR spectra of the obtained PLA homo-polymersand block-copolymers are presented in FIGS. 5A-5C.

Tables 3-5 below present the DSC data of various stereodiblocks (Table3), stereotriblock (Table 4) and stereotetrablocks (Table 5) obtainedwith (R,R)-Lig¹Mg—Cl.

TABLE 3 First run Cooling Second run Composition Tm ΔHm Tc ΔHc Tg Tc/ΔHcTm ΔHm D150-b-L150 219.1 80.5 188 65 56 — 212.7 62.1 — D300-b-L300 218.070.6 183 68 55 — 214.0 67.9 — L400-b-D400 211.8 79.0 135 51 56 — 213.250.4 — D400-b-L400 215.9 71.4 159 57 56 — 209.9 57.0 — L500-b-D500 215.185.4 152 59 58 — 215.1 58.0 — T (° C.); ΔH (J/g)

TABLE 4 First run Cooling Second run Composition Tm ΔHm Tc ΔHc Tg Tc/ΔHcTm ΔHm L100-b-D100-b-L100 206 45 131 40 55 — 207 42 — D100-b-L100-b-D100206 51 135 43 55 — 208 42 — L200-b-D200-b-L200 207 40 130 37 54 — 205 36— D200-b-L200-b-D200 207 49 137 47 52 — 204 44 — L100-b-D100-b-L100 +211 65 141 56 58 — 212 53 D100-b-L100-b-D100 — L200-b-D200-b-L200 + 21168 136 56 57 — 210 49 D200-b-L200-b-D200 — T (° C.); ΔH (J/g)

TABLE 5 First run Cooling Second run Composition Tm ΔHm Tc ΔHc Tg Tc/ΔHcTm ΔHm L50-b-D50-b-L50-b-D50 192 44 118 44 54 — 195.0 45.8 —L100-b-D100-b-L100-b- 208 55 119 60 53 — 200.5 48.8 D100 —L200-b-D200-b-L200-b- 201 71 124 48 58 — 206.8 50.3 D200 — T (° C.); ΔH(J/g)

Polymerizations of the homochiral lactides were run in dichloromethaneat room temperature by adding benzyl alcohol to the {ONNN}Mg—Cl complexfollowed by addition of the lactide. Preliminary runs showed that theaddition of 1 mol equivalent of benzyl alcohol to the {ONNN}Mg—Clsolution followed by addition of 300 mol equivalents of L-LA led to fullconsumption of the monomer within one minute. This corresponds to one ofthe highest activities ever reported for lactide polymerization.

Gel permeation chromatographic (GPC) analysis of the polymer samplesrevealed exceptionally narrow MWD with typical values of Mw/Mn≤1.05, andnumber-average molecular weights (Mn) which coincided with themonomer/initiator molar ratio.

{ONNN}Mg—Cl was found to act as an“immortal polymerization” catalyst,namely, it enabled the growth of more than a single polymer chain byevery magnesium center by simply employing more than a single equivalentof benzyl alcohol.

The PLA samples obtained under the immortal conditions retained verynarrow MWD values, and the measured Mn's were consistent with thecalculated values of monomer/benzyl alcohol molar ratio. The activity ofthe {ONNN}Mg—Cl complex was examined up to L-LA loading of 4300 molequivalents (and 2 mol equivalents of benzyl alcohol). Full monomerconsumption was reached in 6 minutes and the PLLA produced wasmonodisperse and of very high Mn.

While the narrow MWD and expected Mn of the PLA obtained are necessaryrequirements of living polymerization, a truly-living polymerizationalso requires that following the full consumption of the first monomer,the addition of a second portion of (the same or different) monomerwould lead to a continued growth of all polymeryl chains.

200 mol equivalents of L-LA were polymerized with {ONNN}Mg—Cl under theabove conditions, and a second portion of 200 mol equivalents of L-LAwas added only after twelve hours. All 400 mol equivalents were consumedand the PLLA obtained was of narrow MWD and expected Mn. Namely, thiscatalyst hibernates when deprived of monomer and continues growing allpolymeryl chains upon monomer addition.

The synthesis of stereo-diblock copolymers was performed by adding L-LAto a stirring mixture of {ONNN}Mg—Cl and benzyl alcohol indichloromethane, followed by addition of D-LA after several minutes andeventual workup after an identical interval, as illustrated in FIG. 4 .

It was found that PLLA-PDLA diblock copolymers having identical blocklengths each of 150 (2×5 minutes), 300 (2×10 minutes) and even 400 or500 (2×15 minutes) repeat units were readily obtained by this one-potsynthesis. The two monomer enantiomers were fully consumed, and thepolymer samples featured a perfectly isotactic stereo-diblockmicrostructure (rather than a gradient microstructure that would resultfrom an incomplete consumption of the first lactide enantiomer), asshown by the sharp mmm tetrad in their homo-decoupled (HD) ¹H NMRspectra (see, FIG. 5A).

A control experiment that mimics an incomplete first monomer conversionwas run by polymerizing 96 mol equivalents of L-LA, waiting 10 minutesto ascertain a full conversion, and thereafter adding a mixtureconsisting of 100 mol equivalents of D-LA and 4 mol equivalents of L-LAand letting the polymerization proceed to full conversion. HD ¹H NMR ofthis sample showed stereoerrors that were absent from the originaldiblock copolymers, as shown in FIG. 5B, signifying that therein theconversion of the L-LA prior to the addition of the D-LA substantiallyexceeded 96%.

GPC analysis of the short diblock copolymers in THF and the less solublelonger diblock copolymers in chloroform revealed that they had allexhibited narrow molecular weight distributions (Mw/Mn≤1.11) and asexpected Mn's (see, Table 2).

The one-pot methodology described herein is applicable for the synthesisof precise stereo-diblock PLA of any block lengths' ratio, which arecurrently prepared by a laborious and less controlled two-step synthesis(see, for example, Tsuji et al. Macromol. Mater. Eng. 299, 430 (2014)).The possibility that epimerization or trans-esterification sidereactions might be taking place was revoked by a diblockcopolymerization run in which the workup was delayed by 6 hours and yet,neither MWD broadening nor stereoerrors were observed.

Differential scanning calorimetry (DSC) measurements of thestereo-diblock copolymers carried out on cast films revealed verysimilar melting transitions at 215-220° C. for all samples, consistentwith a stereocomplex crystal phase, which was confirmed by X-rayanalysis, as shown in FIG. 4 . The crystallinity degree of the samplesranged from 40 to 60% (melting enthalpies=61-85 J/g).

The melting temperature (Tm) and enthalpy (ΔHm) are among the highestever reported for stereo-diblock PLA copolymers. All samples were foundto completely crystallize from the melt during the cooling DSC run, andthe Tm's of the second heating were practically identical to those ofthe first heating with sample crystallinities remaining high (38-47%).No evidence for homocrystallization was found, even for the longerdiblock samples.

Extending this methodology to a three-step sequential addition affordedisotactic stereo-triblock PLA copolymers. Full monomer consumption wasobserved within 15-30 minutes, giving rise to triblock copolymers ofnarrow MWD's and as-predicted Mn's, as well as precise isotactic blocksconstitution (See FIG. 5C). Different combinations of blocks could be“dialed in” including identical blocks of various lengths, like100L-b-100D-b-100L and 200L-b-200D-b-200L or short-long-short blockslike 150L-b-15D-b-150L (see, Table 2).

DSC analysis of the triblock enantiomers (LDL and DLD) having blocklengths of 100 repeat units revealed that Tm's and ΔHm's (Tm of 206° C.for both, and ΔHm of 41 and 51 J/g for LDL and DLD, respectively) arelower than those of the typical diblock copolymers. This behavior isexpected for copolymers having unpaired enantiomeric blocks which leadto defects for the stereocomplex crystallization. A 1:1 blend of thesetwo enantiomeric triblock copolymers led to enhancement of both the Tm(211° C.) and ΔHm(55 J/g).

Consistently, isotactic stereo-tetrablock PLA copolymers could beprepared by a four-step sequential addition process in a totalpolymerization time of less than 60 minutes, and exhibited all thecharacteristics of precise copolymer structure. DSC analysis ofstereo-tetrablock samples revealed that while their T_(m)'s were similarto those of the analogous triblock copolymers, their Hm were higher by30% than those of triblocks on average. This behavior is consistent withcopolymers of equal number of D-LA and L-LA repeat units.

The synthesis of isotactic PLA copolymers of penta-block, hexa-block andeven octa-block sequences was also demonstrated. Analysis of theconversion of the monomers, and the MWD, Mn and stereoregularity of thepolymers revealed that the penta-block copolymer (5×100) was still ofvery high precision according to all parameters with a very high degreeof isotacticity of P_(m)>0.96.

The data presented herein indicate that a {ONNN}Mg—Cl complex asdescribed herein is capable of forming block-copolymers of precisemicrostructures, and is by far the most living catalyst ever describedfor cyclic ester ring-opening polymerization and is comparable to thehighest living catalysts for any polymerization (such as, for example,reported by Soeriyadi, et al. J. Am. Chem. Soc. 133, 11128 (2011).

The data presented herein show that novel poly(lactic acid) materialsfeaturing isotactic stereo-block microstructures of unprecedentedprecision are obtainable by a one-pot sequential monomer addition to atruly-living polymerization catalyst based on the common and non-toxicmetal magnesium. The methodology provided herein can be utilized forproviding a wide range of tailor-made architectures. The disclosedprocess of preparing block copolymers exemplified herein can bemodified, for example, by employing rac-LA or related cyclic esters, orby synthesizing more elaborate polymeric architectures which consist ofmore than a single polymeryl branch, by employing polyalcohols insteadof benzyl alcohol, as exemplified in Example 4 hereinunder.

Example 3 Block-Polymerization of Lactide and Caprolactone Employing anExemplary {ONNN}Mg-HMDS Complex

General PLA-PCL Block Copolymerization Procedure:

To a solution of the {ONNN}Mg—X complex (pre-catalyst) (2 μmol) indichloromethane (5 mL), benzyl alcohol or 1,4-benzenedimethanol (5 molequivalents) were added and the reaction mixture was stirred at roomtemperature for 2 minutes. Then, ε-caprolactone (ε-CL) was added,followed by either D- or L-lactide, maintaining the necessary delay(e.g., 2-5 minutes) between each addition. The reaction was terminatedby exposing to air and the volatiles were removed under vacuum. Thetacticity and stereoregularity of the copolymer samples were determinedby the homonuclear-decoupled ¹H NMR spectrometry (CDCl₃, 500 MHz) and by¹³C NMR (CDCl₃, 125 MHz).

Table 6 below presents the data obtained for block co-polymerization ofD/L-LA and ε-CL, employing (R,R)-Lig¹Mg-HMDS, in dichloromethane at roomtemperature.

TABLE 6 Inter- val (min- Type Composition ute) M_(n) PDI 1. Di BlockPCL(100)-b-L(100) 7 40770 1.18 2. Di Block PCL(300)-b-L(300) 9 1011001.18 3. Di Block PCL(500)-b-L(500) 10 178300 1.18 4. Di BlockPCL(100)-b-D(100) 7 39700 1.15 5. Di Block PCL(300)-b-D(300) 7 1056001.19 6. Di Block PCL(500)-b-D(500) 7 192000 1.19 7. Di BlockPCL(800)-b-D(800) 8 317200 1.21 8. Tri Block L(100)-b-PCL(100)-b- 681000 1.13 L(100) 9. Tri Block D(100)-b-PCL(100)-b- 5 64000 1.08 D(100)10. Tri Block D(200)-b-PCL(200)-b- 7 111000 1.12 D(200) 11. Tri BlockD(300)-b-PCL(300)-b- 7 135380 1.16 D(300) 12. Tri BlockPCL(100)-b-D(100)-b- 10 58700 1.08 L(100) 13. Tri BlockPCL(200)-b-D(200)-b- 10 105500 1.09 L(200) 14. Tri BlockPCL(300)-b-D(300)-b- 12 164000 1.10 L(300) 15. Tetra BlocksPCL(100)-b-D(100)-b- 12 65000 1.10 L(100)-b-D(100) 16. Penta BlocksD(100)-b-L(100)-b- 11 89560 1.09 PCL(100)-b-L(100)-b- D(100) 17. PentaBlocks D(200)-b-L(200)-b- 12 182400 1.10 PCL(200)-b-L(200)-b- D(200) 18.Penta Blocks D(300)-b-L(300)-b- 15 285500 1.06 PCL(300)-b-L(300)-b-D(300) 19. Penta Blocks L(50)-b-D(50)-b- 9 54100 1.13 PCL(50)-b-D(50)-b-L(50) 20. Penta Blocks L(100)-b-D(100)-b- 11 101300 1.17PCL(100)-b-D(100)-b- L(100) 21. Penta Blocks L(200)-b-D(200)-b- 12142500 1.10 PCL(200)-b-D(200)-b- L(200) 22. Penta BlocksL(300)-b-D(300)-b- 15 302500 1.12 PCL(300)-b-D(300)-b- L(300) 23. PentaBlocks PCL(100)-b-L(100)-b- 13 85800 1.10 D(100) -b-L(100)-b- D(100) 24.Hepta Blocks L(50)-b-D(50)-b-L(50)- 10 82450 1.10 b-PCL(50)-b-L(50)-b-D(50)-b-L(50) 25. Hepta Blocks L(100)-b-D(100)-b- 14 192000 1.12L(100)-b-PCL(100)-b- L(100)-b-D(100)-b- L(100)

The synthesis of stereo-diblock copolymers was performed by adding F-CLto a stirring mixture of {ONNN}Mg-HDMS and benzyl alcohol indichloromethane, followed by addition of L-LA or D-LA after severalminutes and eventual workup after an identical interval.

It was found that PLLA-PCL and PDLA-PCL diblock copolymers havingidentical block lengths repeat units were readily obtained by thisone-pot synthesis. The two monomer enantiomers were fully consumed, andthe polymer samples featured a perfectly regular stereo-diblockmicrostructure.

The three-step sequential addition afforded variable isotacticstereo-triblock copolymers: PCL-PLLA-PCL; PCL-PDLA-PCL; PCL-PLLA-PDLA.Different combinations of blocks could be “dialed in” includingidentical blocks of various lengths, or short-long-short blocks.

Consistently, stereo-tetrablock, penta-block and hepta-block copolymershave been prepared by a sequential addition process, and exhibited allthe characteristics of precise copolymer structure.

The data presented herein indicate that a {ONNN}Mg-HDMS complex asdescribed herein is capable of forming block-copolymers of precisemicrostructures, and is by far the most living catalyst ever describedfor cyclic ester ring-opening polymerization and is comparable to thehighest living catalysts for any polymerization (such as, for example,reported by Soeriyadi, et al. J. Am. Chem. Soc. 133, 11128 (2011).

Notably, block-copolymers exhibiting exceptionally high molecular weightwere obtained.

The data presented herein show that novel plastic materials featuringisotactic stereo-block microstructures of unprecedented precision andlength are obtainable by a one-pot sequential monomer addition to atruly-living polymerization catalyst based on the common and non-toxicmetal magnesium, opening the way for providing an even wide range oftailor-made architectures.

Example 4 Homo-Polymerization and Block-Polymerization EmployingSequential {ONNN}-Mg—X Complexes and a Polyalcohol

Preliminary experiments were made for providing more elaborate polymericarchitectures which consist of more than a single polymeryl branch, byemploying polyalcohols such as poly(ethylene glycol) or pentaerythritol,instead of benzyl alcohol.

The PLA-PCL copolymers having PCL as middle block, see, entries 8-10 intable 7, were prepared using 1,4-benzenedimethanol.

Table 7 below presents the obtained data, and show full lactide (orlactide and caprolactone, entries 3,6) consumption, demonstrating theapplicability of this methodology for attaining complex architectures ofstereoblock copolymers.

TABLE 7 Catalyst Alcohol Composition M_(n) PDI 1 Lig¹Mg—Cl Penta-C[CH₂—O-PLLA(100)]₄ 36700 1.12 erythritol 2 Lig¹Mg—Cl Penta-C[CH₂—O-PLLA(100)- 72340 1.16 erythritol b-PDLA(100)]₄ 3 Lig¹Mg- Penta-C[CH₂—O-PCL(100)]₄ 43250 1.59 HMDS erythritol 4 Lig¹Mg—Cl PEG2000PLLA(100)-b-PEG2000- 27000 1.09 b-PLLA(100) 5 Lig¹Mg—Cl PEG2000PDLA(100)-b- 41500 1.10 PLLA(100)-b-PEG2000- b-PLLA(100)-b- PDLA(100) 6Lig¹Mg- PEG2000 PLLA(100)-b-PCL(100)- 58760 1.18 HMDSb-PEG2000-b-PCL(100)- b-PLLA(100)

Example 5 Syntheses of Magnesium Complexes of Divergent {ONNN} LigandsSyntheses of Divergent {ONNN} Ligands

Divergent monoanionic ligands were prepared (Lig²⁻⁶H, see, FIG. 7 )having alkyl substituents of different steric bulk (H, Me, tBu,adamantly and cumyl) in the ortho- and para-positions of the phenolatearm. The ligands were readily synthesized by single-step procedures inhigh yields, by a modified reductive-amination reaction (Lig^(2,4-6)H)or by the Mannich reaction (Lig³H), employing the commercially-availablebis(2-pyridylmethyl) amine and a commercially- or readily-availablesubstituted phenol/salicylaldehyde. The ligand precursors were obtainedas colourless or yellow powders, and their identities were confirmed byNMR spectroscopy and high-resolution mass spectrometry.

Bis(2-pyridylmethyl)amine was purchased from TCI and used as received.Sodium triacetoxyborohydride was purchased from Strem and used asreceived. 3-Adamantyl-5-methylsalicylaldehyde,3,5-bis(dimethylbenzyl)salicylaldehyde and the ligand precursors Lig³′4Hwere synthesized following previously published procedures [K. Gademannet al., Angew. Chem. Int. Ed., 2002, 41, 3059-3061; A. I. Kochnev etal., Russ. Chem. Bull. Int. Ed., 2007, 56, 1125-1129; D. D. Cox and L.Que, J. Am. Chem. Soc., 1988, 110, 8085-8092; M. J. L. Tschan et al.,Dalton Trans., 2014, 43, 4550-4564].

Synthesis of Lig¹H

This compound was synthesized by modification of a literature procedure[G. P. Connor et al., Inorg. Chem., 2014, 53, 5408-5410].

To a solution of bis(2-pyridylmethyl)amine (720 mg, 3.61 mmol) indichloromethane (40 mL), sodium triacetoxyborohydride (990 mg, 4.67mmol) was added at 0° C. The mixture was stirred at 0° C. for 1 hour,after which salicylaldehyde (440 mg, 3.61 mmol) was added. Afteradditional 4 hours stirring at room temperature, the reaction wasquenched by adding NaHCO₃10% solution (20 mL). The organic phase wasseparated and dried over Na₂SO₄. The solvent was removed under vacuumand the crude product was purified by passing through a plug of silicawith ethyl acetate as eluent. A yellow oil was obtained. The overallyield was 82%.

¹H NMR (CDC₃, 500 MHz): δ 11.09 (brs, 1H, OH), 8.57 (d, 2H, J=4.6 Hz,ArH), 7.62 (td, 2H, J=1.7 Hz, J=7.7 Hz, ArH), 7.34 (d, 2H, J=7.8 Hz,ArH), 7.19-7.14 (m, 3H, ArH), 7.06 (dd, 1H, J=1.3 Hz, J=7.6 Hz, ArH),6.91 (dd, 1H, J=0.7 Hz, J=8.0 Hz, ArH), 6.77 (td, 1H, J=1.0 Hz, J=7.4Hz, ArH), 3.88 (s, 4H, CH₂), 3.80 (s, 2H, CH₂).

¹³C NMR (CDCl₃, 125 MHz): δ 158.43 (C), 157.73 (C), 149.07 (CH), 136.91(CH), 130.30 (CH), 129.20 (CH), 123.37 (CH), 122.95 (C), 122.36 (CH),119.00 (CH), 116.68 (CH), 59.25 (CH₂), 57.10 (CH₂).

HRMS (ESI): Calc for C₁₉H₁₉N₃O: 305.1528, found: 328.1428 (M−Na+).

Synthesis of Lig⁵H

This compound was synthesized according to the procedure described aboveemploying 3-adamantyl-5-methylsalicylaldehyde. A yellow solid wasobtained in an overall yield of 90%.

¹H NMR (CDC₃, 500 MHz): δ 10.45 (brs, 1H, OH), 8.56 (d, 2H, J=4.6 Hz),7.63 (td, 2H, J=1.7 Hz, J=7.7 Hz, ArH), 7.33 (d, 2H, J=7.8 Hz, ArH),7.15 (dd, 2H, J=4.8 Hz, J=7.6 Hz, ArH), 6.94 (d, 1H, J=1.6 Hz, ArH),6.71 (d, 1H, J=1.4 Hz, ArH), 3.85 (s, 4H, CH₂), 3.76 (s, 2H, CH₂), 2.23(s, 3H, CH₃), 2.20 (brs, 6H, Ad), 2.08 (brs, 6H, Ad), 1.83 (d, 3H,J=12.0 Hz, Ad), 1.78 (d, 3H, J=12.0 Hz, Ad).

¹³C NMR (CDCl₃, 125 MHz): δ 158.23 (C), 154.40 (C), 149.14 (CH), 136.84(C), 136.76 (CH), 128.45 (CH), 127.21 (C), 126.93 (CH), 123.76 (CH),122.83 (C), 122.33 (CH), 59.45 (CH₂), 58.03 (CH₂), 40.68 (C), 40.54(CH₂), 37.41(CH₂), 36.98 (CH), 29.40 (CH₂), 20.92 (CH₃).

HRMS (ESI): Calc for C₃H₃₅N₃O: 453.2780, found: 454.2854 (MH+).

Synthesis of Lig⁶H

This compound was synthesized according to the procedure described aboveemploying 3,5-bis(dimethylbenzyl)salicylaldehyde. A yellow solid wasobtained in an overall yield of 94%.

¹H NMR (CDC₃, 500 MHz): δ 10.34 (brs, 1H, OH), 8.45 (d, 2H, J=4.5 Hz,ArH), 7.47 (td, 2H, J=1.8 Hz, J=7.7 Hz, ArH), 7.26-7.21 (m, 6H, ArH),7.18-7.14 (m, 3H, ArH), 7.14-7.08 (m, 3H, ArH), 6.92 (d, 2H, J=7.8 Hz,ArH), 6.76 (d, 1H, J=2.3 Hz, ArH), 3.68 (s, 2H, CH₂), 3.67 (s, 2H, CH₂),1.68 (s, 6H, CH₃), 1.67 (s, 6H, CH₃).

¹³C NMR (CDC₃, 125 MHz): δ 157.88 (C), 153.54 (C), 151.94 (C), 151.54(C), 148.95 (CH), 140.02 (C), 136.81 (CH), 135.39 (C), 128.01 (CH),127.74 (CH), 126.90 (CH), 126.67 (CH), 125.93 (CH), 125.53 (CH), 125.17(CH), 124.71 (CH), 124.02 (CH), 122.25 (CH), 121.83 (C), 59.15 (CH₂),58.24 (CH₂), 42.60 (C), 42.25 (C), 31.25 (CH₃), 29.63 (CH₃).

HRMS (ESI): Calc for C₃₇H₃₉N₃O: 541.3093, found: 542.3177 (MH+).

Syntheses of Divergent {ONNN}-Mg—Cl Complexes

The bulky ligand precursors Lig⁴-6H were reacted with one mol equivalentof benzyl magnesium chloride in toluene at room temperature, accordingto a previously described procedure [T. Rosen et al, J. Am. Chem. Soc.,2016, 138, 12041-12044] and yielded the corresponding chloro-magnesiumcomplexes as yellow powders in high to quantitative yields (see, FIG. 7). ¹H-NMR spectroscopy (in CDCl₃) revealed a single set of peakssignifying mononuclear complexes of the type Lig^(n)Mg—Cl obtained assingle stereoisomers of Cs-symmetry (FIG. 8 , top panel). The magnesiumcomplexes of the non-bulky divergent ligand precursors Lig^(2,3)H wereprepared likewise, and yielded the corresponding complexes in highyields as yellow powders as well. The ¹H-NMR spectra of these twocomplexes displayed different characteristics including two sets ofpeaks for the two pyridine rings and three AB systems for the three CH₂bridges. This reduced symmetry is attributed to the formation ofdinuclear magnesium complexes of the type [(μ-Lig^(n))Mg—Cl]₂ for thesesterically non-encumbered ligands (see, FIG. 7 , FIG. 8 , bottom panel,FIGS. 9A and 9B) having either Ci- or Cs-averaged symmetry.

Single crystals of the complexes [(μ-Lig²)Mg—Cl]₂ and [(μ-Lig³)Mg—Cl]₂were grown from dichloromethane solutions at 35° C., and their molecularstructures were determined by X-ray diffraction studies. The twocomplexes were isostructural, featuring dinuclear chloro-magnesiumcomplexes of octahedral geometry in which the phenolate oxygens of thetwo ligand units bridge between the two magnesium atoms, thus supportingthe NMR findings (see, FIGS. 9A and 9B). A crystallographic C₁-symmetryof the two complexes dictates a planar Mg—O—Mg—O ring, and the Mg—O(Ph)bond lengths are only slightly different, being 2.032° A and 2.061° Afor [(μ-Lig²)Mg—Cl]₂ and 2.026° A and 2.062° A for [(μ-Lig¹)Mg—Cl]₂.

The molecular structure of previously reported magnesium enolato complexof Lig⁴ featured a pentacoordinate mononuclear magnesium centre,supporting a mononuclear structure of Lig⁴⁻⁶Mg—Cl. Further evidence forthese different coordination modes was provided by high-resolution massspectrometry (HRMS) analysis, which supported the formation of theproposed mononuclear and dinuclear structures for Lig⁴⁻⁶Mg—Cl andLig^(2,3)Mg—Cl, respectively.

Synthesis of [(μ-Lig²)Mg—Cl]₂

To a stirred solution of Lig²H (80 mg, 0.26 mmol) in toluene (2 mL), wasadded a solution of BnMgCl (0.26 mL, 1M diethyl ether solution)drop-wise. The resulting mixture was stirred at room temperature for 30minutes until a precipitate appeared. The solvent was thereafter removedunder vacuum and the residue was washed with pentane to give a yellowsolid in 61% yield. Crystals suitable for X-ray diffraction were grownfrom dichloromethane solution at −30° C.

¹H NMR (CDC₃, 500 MHz): δ 8.95 (d, 2H, J=14.3 Hz, ArH), 7.73 (t, 1H,J=7.2 Hz, ArH), 7.35 (d, 1H, J=7.3 Hz, ArH), 7.23 (t, 1H, J=7.0 Hz,ArH), 7.04 (t, 1H, J=5.8 Hz, ArH), 6.77 (t, 1H, J=5.8 Hz, ArH), 6.62 (t,2H, J=8.3 Hz, ArH), 6.42 (d, 1H, J=12.3 Hz, CH₂), 6.19 (t, 1H, J=7.0 Hz,ArH), 6.05 (t, 1H, J=7.0 Hz, ArH), 5.23 (d, 1H, J=15.0 Hz, CH₂), 4.85(d, 1H, J=7.6 Hz, ArH), 4.10 (d, 1H, J=15.1 Hz, CH₂), 3.82 (d, 1H,J=15.0 Hz, CH₂), 3.49 (d, 1H, J=15.1 Hz, CH₂), 3.38 (d, 1H, J=12.2 Hz,CH₂).

¹³C NMR (CDC₃, 125 MHz): δ 163.61(C), 156.45 (C), 156.33 (C), 151.69(CH), 150.92 (CH), 138.40(CH), 137.14 (CH), 129.97 (CH), 128.25 (CH),127.65 (C), 122.99 (CH), 122.72 (CH), 122.17 (CH), 120.68 (CH), 119.08(CH), 115.40 (CH), 64.50 (CH₂), 61.57 (CH₂), 61.49 (CH₂).

HRMS (APPI): Calc for C₃₈H₃₆Cl₂Mg₂N₆O₂: 726.1978, found: 691.2275([M−Cl]⁺).

Crystal Data for Complex [(u-Lig²)Mg—Cl]₂.2CH₂Cl₂. C₁₉H₁₈ClN₃OMg,2CH₂Cl₂; M=533.97; monoclinic; space group C₂/c; a=24.0022(18) Å,b=8.6136(6) Å, c=25.556(3) Å, =116.047(3°), V=4746.9(7) Å³; T=110(2) K;Z=8; Dc=1.494 g cm⁻³; (MoKα)=0.658 mm⁻¹; R1=0.0516 and wR2=0.0972 for4733 reflections with I>2σ (I); R1=0.0391 and wR2=0.0912 for all 3904unique reflections. CCDC No. 1537631. See, FIG. 9A.

Synthesis of [(μ-Lig³)Mg—Cl]₂

To a stirred solution of Lig³H (76 mg, 0.23 mmol) in toluene (2 mL), wasadded a solution of BnMgCl (0.23 mL, 1M diethyl ether solution)drop-wise. The resulting mixture was stirred at room temperature for 1hour until a precipitate appeared. The solvent was thereafter removedunder vacuum and the residue was washed with pentane to give a yellowsolid in 74% yield.

¹H NMR (CDC₃, 500 MHz): δ 9.25 (d, 1H, J=5.7 Hz, ArH), 9.12 (d, 1H,J=5.7 Hz, ArH), 7.69 (td, 1H, J=1.7 Hz, J=7.6 Hz, ArH), 7.28 (d, 1H,J=7.7 Hz, ArH), 7.16 (td, 1H, J=1.7 Hz, J=7.6 Hz, ArH), 7.07 (t, 1H,J=6.4 Hz, ArH), 6.76 (t, 1H, J=6.4 Hz, ArH), 6.56 (d, 1H, J=11.9 Hz,CH₂), 6.54 (d, 1H, J=2.0 Hz, ArH), 6.37 (d, 1H, J=7.7 Hz, ArH), 5.96 (d,1H, J=1.6 Hz, ArH), 4.92 (d, 1H, J=14.9 Hz, CH₂), 3.95 (d, 1H, J=14.9Hz, CH₂), 3.61 (d, 1H, J=14.9 Hz, CH₂), 3.40 (d, 1H, J=15.1 Hz, CH₂),3.37 (d, 1H, J=13.9 Hz, CH₂), 1.94 (s, 3H, CH₃), 0.95 (s, 3H, CH₃).

¹³C NMR (CDCl₃, 125 MHz): δ 158.63 (C), 156.75 (C), 155.91(C), 152.25(CH), 149.70 (CH), 138.49 (CH), 136.62 (CH), 130.97 (CH), 129.13 (CH),126.85 (C), 126.79 (C), 124.08 (C), 123.41 (CH), 122.75 (CH), 121.65(CH), 120.06 (CH), 65.24 (CH₂), 62.29 (CH₂), 61.47 (CH₂), 20.33 (CH₃),14.21 (CH₃).

HRMS (APPI): Calc for C₄₂H₄₄Cl₂Mg₂N₆O₂: 782.2604, found: 747.2916([M−Cl]⁺).

Crystal Data for Complex [(μ-Lig³)MgCl]₂.5CH₂Cl₂. C₄₂H₄₄Cl₂N₆O₂Mg₂,5CH₂Cl₂; M=1208.98; monoclinic; space group C₂/c; a=27.2980(18) Å,b=14.9001(12) Å. c=16.8775(10) Å. β=124.630(2)°, V=5648.6(7) Å³;T=110(2) K; Z=4; Dc=1.422 g cm⁻³; (Mo Kα)=0.653 mm⁻¹; R1=0.0702 andwR2=0.0567 for 5026 reflections with I>2σ (I); R1=0.1604 and wR2=0.1488for all 4116 unique reflections. CCDC No. 1537632. See, FIG. 9B.

Synthesis of Lig⁴Mg—Cl

To a stirred solution of Lig⁴H (92 mg, 0.22 mmol) in toluene (2 mL), wasadded a solution of BnMgCl (0.22 mL, 1M diethyl ether solution)drop-wise. The resulting mixture was stirred at room temperature for 1hour until a precipitate appeared. The solvent was thereafter removedunder vacuum and the residue was washed with pentane to give a yellowsolid in 90% yield.

¹H NMR (CDC₃, 500 MHz): δ 9.35 (d, 2H, J=5.1 Hz, ArH), 7.84 (td, 2H,J=1.4 Hz, J=7.5 Hz, ArH), 7.41 (t, 2H, J=6.5 Hz, ArH), 7.29 (d, 2H,J=7.7 Hz, ArH), 7.17 (d, 1H, J=2.5 Hz, ArH), 6.80 (d, 1H, J=2.5 Hz,ArH), 4.09 (d, 2H, J=15.7 Hz, CH₂), 3.82 (d, 2H, J=15.7 Hz, CH₂), 3.75(brs, 2H, CH₂), 1.43 (s, 9H, C(CH₃)₃), 1.24 (s, 9H, C(CH₃)₃).

¹³C NMR (CDCl₃, 125 MHz): δ 163.35 (C), 157.00 (C), 151.75 (CH), 139.99(CH), 138.58 (C), 134.07 (C), 129.19 (CH), 128.38 (CH), 125.45 (CH),125.33 (CH), 124.30 (CH), 124.16 (CH), 123.18 (CH), 120.99 (C), 60.92(CH₂), 58.45 (CH₂), 35.36 (C), 33.95 (C), 32.06 (CH₃), 29.78 (CH₃).

HRMS (APPI): Calc for C₂₇H₃₄N₃OClMg: 475.2241, found: 476.2302 (MH+).

Synthesis of Lig⁵Mg—Cl

To a stirred solution of Lig⁵H (104 mg, 0.23 mmol) in toluene (2 mL),was added a solution of BnMgCl (0.23 mL, 1M diethyl ether solution)drop-wise. The resulting mixture was stirred at room temperature for 1hour until a precipitate appeared. The solvent was thereafter removedunder vacuum and the residue was washed with pentane to give a yellowsolid in 91% yield.

¹H NMR (CDC₃, 500 MHz): δ 9.38 (d, 2H, J=4.9 Hz, ArH), 7.84 (td, 2H,J=1.7 Hz, J=7.7 Hz, ArH), 7.42 (t, 2H, J=6.5 Hz, ArH), 7.28 (d, 2H,J=7.8 Hz, ArH), 6.88 (d, 1H, J=2.1 Hz, ArH), 6.64 (d, 1H, J=2.0 Hz,ArH), 4.07 (d, 2H, J=15.8 Hz, CH₂), 3.79 (d, 2H, J=15.7 Hz, CH₂), 3.73(brs, 1H, CH₂), 2.21 (d, 6H, J=2.0 Hz, Ad), 2.18 (s, 3H, CH₃), 2.04(brs, 3H, Ad), 1.87 (d, 3H, J=11.3 Hz, Ad), 1.72 (d, 3H, J=11.7 Hz, Ad).

¹³C NMR (CDC₃, 125 MHz): δ 163.43 (C), 156.99 (C), 151.85, (CH), 140.03(CH), 139.74 (C), 129.19 (CH), 129.11 (CH), 128.38 (CH), 127.80 (CH),125.45 (CH), 124.20 (CH), 123.16 (CH), 122.13 (C), 120.63 (C), 60.35(CH₂), 58.29 (CH₂), 40.21 (CH₂), 37.61 (CH₂), 37.21 (C), 29.59 (CH₃),20.89 (CH).

HRMS (APPI): Calc for C₃₀H₃₄N₃OClMg: 511.2241, found: 512.2300 (MH⁺).

Synthesis of Lig⁶Mg—Cl

To a stirred solution of Lig⁶H (110 mg, 0.20 mmol) in toluene (2 mL),was added a solution of BnMgCl (0.20 mL, 1M diethyl ether solution)drop-wise. The resulting mixture was stirred at room temperature for 1hour until a precipitate appeared. The solvent was thereafter removedunder vacuum and the residue was washed with pentane to give a yellowsolid in 88% yield.

¹H NMR (CDC₃, 500 MHz): δ 9.11 (d, 2H, J=4.5 Hz, ArH), 7.79 (td, 2H,J=1.7 Hz, J=7.7 Hz, ArH), 7.36 (t, 2H, J=6.2 Hz, ArH), 7.25-7.18 (m, 7H,ArH), 7.13-7.11 (m, 3H, ArH), 6.77 (t, 2H, J=7.3 Hz, ArH), 6.63 (d, 1H,J=2.5 Hz, ArH), 6.58 (t, 1H, J=7.2 Hz, ArH), 3.75 (d, 2H, J=15.5 Hz,CH₂), 3.58 (d, 4H, J=15.5 Hz, CH₂), 1.69 (brs, 6H, CH₃), 1.65 (s, 6H,CH₃).

¹³C NMR (CDCl₃, 125 MHz): δ 162.23 (C), 156.68 (C), 152.91 (C), 152.76(C), 151.96 (CH), 139.73 (CH), 138.77 (C), 133.24 (C), 127.74 (CH),127.22 (CH), 126.99 (CH), 126.74 (CH), 126.08 (CH), 126.04 (CH), 125.13(CH), 123.87 (CH), 123.83 (CH), 122.88 (CH), 121.07 (C), 60.00 (CH₂),42.37 (C), 42.30 (C), 31.38 (CH₃).

HRMS (APPI): Calc for C₃₇H₃₈N₃OClMg: 599.2554, found: 600.2634 (MH+).

Example 6 Homo-Polymerization and Block-Polymerization of PLa EmployingLig²⁻⁶Mg—Cl

General Homo-Polymerization Procedure:

To a solution of the divergent Mg complex (0.01 mmol) in dichloromethane(5 mL), benzyl alcohol (either none or 0.01-0.04 mmol) was added, andthe reaction mixture was stirred at room temperature for 2 minutes.Then, L-lactide (432 mg, 3 mmol) was added, and the reaction was stirredat room temperature. After the desired time, the reaction was terminatedby exposing to air and the volatiles were removed under vacuum.

General Block-Polymerization Procedure:

To a solution of the divergent Mg complex (0.01 mmol) in dichloromethane(5 mL), benzyl alcohol (2 mol equivalents) was added and the reactionmixture was stirred at room temperature for 2 minutes. Then, D-Lactideand L-Lactide were sequentially added, each separately, maintaining thenecessary delay (5-10 minutes) between each addition. The reaction wasterminated by exposing to air and the volatiles were removed undervacuum.

Polymerization Results:

Tables 8 and 9 present the data obtained for homo-polymerization of L-LA(Table 8) and block co-polymerization of L-LA and D-LA (Table 9)employing Lig²⁻⁶Mg—Cl in dichloromethane at room temperature.

TABLE 8 Time Entry Initiator [I]/[BnOH]/[LA] (min) Conv.^(a) Mn calc^(b)Mn^(c) PDI^(d) 7. [(μ-Lig²)Mg—Cl]₂ 1/1/300 15 0.90 38,880 30,397 1.08 8.[(μ-Lig²)Mg—Cl]₂ 1/2/600 20 0.91 39,312 32,478 1.08 9. [(μ-Lig²)Mg—Cl]₂1/10/1000 20 0.97 13,968 15,023 1.05 10. [(μ-Lig³)Mg—Cl]₂ 1/1/300 150.88 38,016 39,150 1.07 11. [(μ-Lig³)Mg—Cl]₂ 1/10/1000 20 0.90 12,96010,780 1.06 12. Lig⁴Mg—Cl 1/1/300 5 0.98 42,336 33,940 1.04 13.Lig⁴Mg—Cl 1/10/1000 5 0.99 14,256 13,860 1.04 14. Lig⁴Mg—Cl 1/1/1000 100.98 141,120 86,597 1.06 15. Lig⁵Mg—Cl 1/1/300 2 0.98 42,336 46,527 1.0816. Lig⁵Mg—Cl 1/4/600 3 0.98 21,168 20,155 1.04 17. Lig⁵Mg—Cl 1/1/1000 40.97 139,680 111,510 1.05 18. Lig⁵Mg—Cl 1/10/1000 2 0.98 14,112 13,5401.04 19. Lig⁵Mg—Cl 1/1/2000 5 0.96 276,480 271,452 1.06 20. Lig⁶Mg—Cl1/1/300 5 0.95 41,040 35,860 1.08 21. Lig⁶Mg—Cl 1/10/1000 10 0.95 13,68012,950 1.04 22. Lig⁶Mg—Cl 1/1/1000 10 0.91 131,140 123,450 1.07 23.[(μ-Lig²)Mg—Cl]₂ 1/0/300 15 0.42 18.144 27,369 1.20 24. [(μ-Lig³)Mg—Cl]₂1/0/300 15 0.87 37,584 103,378 1.27 25. Lig⁴Mg—Cl 1/0/300 5 0.93 40,176309,139 1.26 26. Lig⁵Mg—Cl 1/0/300 10 0.93 40,176 297,372 1.20 27.Lig⁶Mg—Cl 1/0/300 5 0.88 38,016 211,172 1.35 ^(a)Determined by ¹H NMRspectroscopy (500 MHz). ^(b)Calculated from monomer conversion assumingfull benzyl alcohol participation or full catalyst activation. Valuesare given in g mol−1 ^(c)Mn was determined by GPC analysis with THF aseluent calibrated with polystyrene standards and multiplied by acorrection factor of 0.58. ^(d)PDI: polydispersity index (Mw/Mn).Determined by GPC analysis.

TABLE 9 Time Mn Initiator Type Composition (min)^(b) Conv.^(c) Pm^(d)calc^(e) Mn^(f) PDI^(g) Lig⁴Mg—Cl Di Block L(100)-b-D(100)10 >0.98 >0.99 28800 26700 1.11 Lig⁴Mg—Cl Di Block L(200)-b-D(200)10 >0.98 >0.99 57600 62670 1.20 Lig⁴Mg—Cl Di Block L(300)-b-D(300)20 >0.98 >0.99 86400 66480 1.34 Lig⁵Mg—Cl Di Block L(100)-b-D(100)10 >0.98 >0.99 28800 22900 1.06 Lig⁵Mg—Cl Di Block L(200)-b-D(200)10 >0.98 >0.99 57600 62900 1.04 Lig⁵Mg—Cl Di Block L(300)-b-D(300)11 >0.98 >0.99 86400 85800 1.04 Lig⁵Mg—Cl Di Block L(400)-b-D(400)12 >0.98 >0.99 115200 113670 1.06 Lig⁵Mg—Cl Di Block L(500)-b-D(500)13 >0.98 >0.99 144000 149110 1.07 Lig⁵Mg—Cl Di Block L(800)-b-D(800)20 >0.98 >0.99 228100 202300 1.09 Lig⁵Mg—Cl Tri Block L(100)-b-D(100)-b-15 >0.98 0.98 43200 45860 1.08 L(100) Lig⁵Mg—Cl Tri BlockL(200)-b-D(200)-b- 16 >0.98 0.98 86400 88940 1.13 L(200) Lig⁵Mg—Cl TriBlock L(300)-b-D(300)-b- 18 >0.98 0.98 129600 120590 1.12 L(300)Lig⁵Mg—Cl Tetra L(100)-b-D(100)-b- 22 >0.98 0.97 57600 64690 1.10 BlockL(100)-b-L(100) Lig⁵Mg—Cl Tetra L(200)-b-D(200)-b- 24 >0.98 0.96 115200104230 1.13 Block L(200)-b-L(200) Lig⁵Mg—Cl Tetra L(300)-b-D(300)-b-24 >0.98 0.96 172800 166100 1.10 Block L(300)-b-L(300) ^(b)Totalpolymerization time given in minutes. 5-15 minutes were maintainedbetween each monomer addition, depending on the monomer amount andlength of polymer chain. ^(c)Determined by ¹H NMR spectroscopy (500MHz). ^(d)Pmeso: the probability of a meso linkage between lactideunits. Determined by the ¹H homonuclear-decoupled NMR spectrometry(CDCl₃, 500 MHz) and by ¹³C NMR (CDCl₃, 125 MHz). ^(e)Calculated frommonomer conversion assuming full benzyl alcohol participation. Valuesare given in g mol−1 ^(f)Mn was determined by GPC analysis with CHCl3 aseluent calibrated with polystyrene standards and multiplied by acorrection factor of 0.58. ^(g)PDI: polydispersity index (Mw/Mn).Determined by GPC analysis.

Tables 10-12 below present the DSC data of various stereodiblocks (Table10), stereotriblock (Table 11) and stereotetrablocks (Table 12) obtainedwith Lig^(4,5)Mg—Cl.

TABLE 10 DSC analysis of stereo-dibiocks. First run Cooling Second runInitiator Composition Tm ΔHm Tc ΔHc Tg Tc/ΔHc Tm ΔHm Lig⁴Mg—Cl L(100)-b-213 75 140 58 56 — 212 58 D(100) Lig⁴Mg—Cl L(200)-b- 213 64 117 47 56 —211 48 D(200) Lig⁵Mg—Cl L(100)-b- 212 59 132 46 58 — 210 42 D(100)Lig⁵Mg—Cl L(200)-b- 211 66 135 52 62 — 213 50 D(200) Lig⁵Mg—Cl L(300)-b-214 76 127 49 58 — 205 51 D(300) Lig⁵Mg—Cl L(400)-b- 210 87 139 60 59106/7 213 61 D(400) Lig⁵Mg—Cl L(500)-b- 214 79 153 54 58 101/3 211 51D(500) Lig⁵Mg—Cl L(800)-b- 214 67 154 43 57 — 216 44 D(800)

TABLE 11 DSC analysis of stereo-triblocks. First run Cooling Second runInitiator Composition Tm ΔHm Tc ΔHc Tg Tc/ΔHc Tm ΔHm Lig⁵Mg—Cl L(100)-b-202 36 106 4 55 99/25  196 29 D(100)-b- L(100) Lig⁵Mg—Cl L(200)-b- 20541 115 23 58  98/12.5 200 33 D(200)-b- L(200) Lig⁵Mg—Cl L(300)-b- 201 40108 11 58 101/21.3 197 31 D(300)-b- L(300)

TABLE 12 DSC data of stereo-tetrablocks. First run Cooling Second runInitiator Composition Tm ΔHm Tc ΔHc Tg Tc/ΔHc Tm ΔHm Lig⁵Mg—Cl L(100)-b-202 49 115 22 59  97/21 204 43 D(100)-b- L(100)-b- D(100) Lig⁵Mg—ClL(200)-b- 205 56 119 37 57 97/9 201 39 D(200)-b- L(200)-b- D(200)Lig⁵Mg—Cl L(300)-b- 179 18 — — 57 140/5  185 6 D(300)-b- L(300)-b-D(300)

Polymerization runs were performed in dichloromethane solution at RT byadding the lactide to the Lig^(n)Mg—Cl complex as catalyst and benzylalcohol as initiator. Under these conditions, polymerization of 300 molequivalents of lactide by the mononuclear complexes Lig⁴⁻⁶Mg—Cl led toalmost full consumption of the monomer within 2-5 minutes (See Table 8).These complexes represent some of the highest activities ever reportedfor lactide polymerization.

The PLLA samples obtained were characterized by gel permeationchromatography (GPC) analysis and were found to have remarkably low PDIvalues of ≤1.08, with molecular weights (Mn) in agreement with themonomer/initiator molar ratios. The performance of these catalysts wasalso explored under ‘immortal conditions’, (namely, underinitiator/catalyst ratio>1, which may lead to the production of morethan a single polymer chain per catalyst unit) which led to PLLA sampleswith very narrow PDIs and M_(n) values consistent with monomer/benzylalcohol initiator ratios. Monomer loadings of up to 2000 mol equivalentswere attempted giving almost full consumption after 5 minutes, andyielding monodisperded PLLA of high Mn. These divergent {ONNN}Mg—Clcomplexes were found to be highly active ROP catalysts of L-LA even inthe absence of benzyl alcohol.

Stereo-di-block copolymers having block lengths of up to 500 repeatunits each were easily prepared in short periods of time of about 10minutes (see, Table 9). These stereo-diblock copolymers featured verynarrow PDIs and their molecular weights coincided with themonomer/initiator ratios according to GPC analysis. This wasparticularly valid for LigMg—Cl, featuring the adamantyl-phenolate groupwhich enabled the synthesis of stereo-diblock copolymers of PDI of≤1.07, and very high block integrities according to their very highdegrees of isotacticity (P_(m)≥0.98). Evidently, the shortpolymerization times kept the side reactions to a minimum.

The synthesis of longer blocks was also performed: an L(800)-b-D(800)stereo-diblock copolymer was prepared in 20 minutes, and featured veryhigh block integrity according to GPC and NMR characterization.

Regardless of block lengths, both melting temperatures and enthalpies(Tm, ΔHm) have high values which range, in the first DSC heating run,from 211 to 215° C., and from 59 to 87 J/g, respectively. These Tm andΔHm values support the high copolymer stereoregularities and the assumedhigh block integrity of the copolymers. This assumption is also validfor the exceptionally long stereo-diblock copolymer L(800)-b-D(800),whose Tm and ΔHm are comparable with those of the shorter copolymers.

All the diblock copolymers crystallized either from the polymerizationsolution, DCM solution or melt during DSC cooling run, and are instereocomplex crystal form. The L(800)-b-D(800) stereo-diblock copolymeris assumed to be the first example of a PLLA-PDLA system having Mw>200kDa (either PLLA-PDLA blends or L-LA/D-LA stereo-diblock copolymers)which fully crystallizes in the stereocomplex form only, rather than asa mixture with the homochiral form. Aiming to validate the assumptionthat the isotactic stereo-block microstructure is a prerequisite for thecrystallization in the stereocomplex phase for polymers of such highmolecular weights, high molecular-weight PLLA and PDLA homochiralsamples were prepared and mixed in a 1:1 ratio in DCM solution, castedfilms were casted therefrom, and analyzed with WAXD. Samples of PLLA andPDLA of about 800 repeat units corresponding to each block of theL(800)-b-D(800) stereo-diblock copolymer, as well as samples of about1600 repeat units, were synthesized and tested.

FIG. 10 compares the WAXD patterns of the films, annealed at 100° C. for10 minutes, of the L(800)-b-D(800) stereo-diblock copolymer and the twohomochiral polymer mixtures. The diblock copolymer pattern only showsthe reflections of the stereocomplex crystal form (at 20 of about 12,21, 24) while the spectra of the two mixtures only show the reflectionsof the homochiral crystal form (at 2θ of about 16.8, 19, 22.4_),supporting the above assumption. Notably, the L(800)-b-D(800)stereo-diblock copolymer has a high degradation temperature of 354° C.(TDTG, valued by the weight loss derivative maximum), the highest amongthe copolymers prepared, due to the unzipping depolymerization mechanismoperating during degradation. The TDTG of the stereo-diblock copolymersincreases linearly with Mn for molecular weights ranging from 20 to 150kDa, while for higher Mns it reaches the plateau value of 350° C. (datanot shown).

The synthesis of higher stereo-n-block copolymers, namely, stereo tri-and tetra-block copolymers was performed by sequential monomer additionsaccording to the above conditions and employing Lig⁴Mg—Cl. Surprisingly,this catalyst enabled the synthesis of stereo-n-block (n=3, 4)copolymers of different block lengths whose integrity was very highjudging by their high degrees of isotacticity, (P_(m)≥0.96).

Although the invention has been described in conjunction with specificembodiments thereof, it is evident that many alternatives, modificationsand variations will be apparent to those skilled in the art.Accordingly, it is intended to embrace all such alternatives,modifications and variations that fall within the spirit and broad scopeof the appended claims.

It is the intent of the applicant(s) that all publications, patents andpatent applications referred to in this specification are to beincorporated in their entirety by reference into the specification, asif each individual publication, patent or patent application wasspecifically and individually noted when referenced that it is to beincorporated herein by reference. In addition, citation oridentification of any reference in this application shall not beconstrued as an admission that such reference is available as prior artto the present invention. To the extent that section headings are used,they should not be construed as necessarily limiting. In addition, anypriority document(s) of this application is/are hereby incorporatedherein by reference in its/their entirety.

What is claimed is:
 1. A process of ring opening polymerization of acyclic ester, the process comprising contacting a plurality of monomersof said cyclic ester with a catalyst system comprising an organometallicmagnesium complex, said organometallic magnesium complex comprising aMg—X unit and a divergent {ONNN} ligand in coordination with said Mg—X.2. The process of claim 1, being for preparing a polyester.
 3. Theprocess of claim 1, wherein said cyclic ester is a lactide.
 4. Theprocess of claim 1, wherein said magnesium complex is represented byFormula IIA or IIB:

wherein: the dashed line represents a coordinative bond; M is magnesium;X is a monoanionic ligand, said monoanionic ligand being other thanalkoxy or aryloxy; B_(A), B_(B) and B_(C) are each independently abridging moiety of 1 to 12 carbon atoms; R₅₁ and R₅₂ are eachindependently hydrogen, alkyl, cycloalkyl, aryl or alternatively, one orboth of R₅₁ and R₅₂ form together, optionally with one or more carbonatoms in B_(C), a heteroalicyclic or heteroaromatic, 5 to 7-memberedring; and R₅₃ and R₅₄ are each independently hydrogen, alkyl,cycloalkyl, aryl or alternatively, one or both of R₅₃ and R₅₄ formtogether with one or more carbon atoms in B_(B), a heteroalicyclic orheteroaromatic, 5 to 7-membered ring.
 5. The process of claim 4, whereinX is other than alkoxy or aryloxy.
 6. The process of claim 4, wherein Xis selected from halo and amine.
 7. The process of claim 4, wherein atleast one of R₄₁ and R₄₂ is a bulky rigid alkyl.
 8. The process of claim1, wherein said polymer is a block copolymer comprising a plurality ofunits, at least two of said units independently comprise a plurality ofpolymerized monomers of a cyclic ester, at least one unit of said atleast two units comprises a plurality of polymerized monomers of a firstcyclic ester, and at least one another unit of said at least two unitscomprises a plurality of polymerized monomers of a second cyclic ester,said second cyclic ester differing from said first cyclic ester by astereoconfiguration and/or a chemical composition, the processcomprising: sequentially contacting a plurality of monomers of saidfirst cyclic ester and a plurality of monomers of said second cyclicester with said catalyst system comprising an initiator and anorganometallic magnesium complex comprising a Mg—X unit and a divergent{ONNN} ligand in coordination with said Mg—X, to thereby sequentiallyeffect a ring opening polymerization of said first cyclic ester and ofsaid second cyclic ester.
 9. The process of claim 8, wherein the blockcopolymer comprises from 2 to units.
 10. The process of claim 8, whereinat least two units in said plurality of units differ from one another bya number of said polymerized monomers.
 11. The process of claim 8,wherein at least 90%, or at least 95% or at least 96% or at least 98% orat least 99% of polymerized monomers in each of said units feature thesame stereoconfiguration and/or chemical composition.
 12. The process ofclaim 8, wherein said block copolymer is a stereoblock copolymercomprising at least one unit of polymerized monomers of said firstcyclic ester and at least one unit of polymerized monomers of a secondcyclic ester, said first cyclic ester featuring a firststereoconfiguration and said second cyclic ester featuring a secondstereoconfiguration, said first and said second stereoconfigurationsbeing different from one another, the process comprising: sequentiallycontacting a plurality of monomers of said first cyclic ester featuringsaid first stereoconfiguration and a plurality of monomers of saidsecond cyclic ester featuring said second stereoconfiguration with saidcatalyst system.
 13. The process of claim 12, wherein at least 90%, orat least 95% or at least 96% or at least 98% or at least 99% of saidpolymerized monomers in each of said units feature the samestereoconfiguration.
 14. The process of claim 8, wherein at least one ofsaid first and second cyclic esters is a lactide or a lactone.
 15. Anorganometallic complex represented by Formula III:

wherein: the dashed line represents a coordinative bond; M is magnesium;X is a monoanionic ligand; m, n and q are each independently an integerof from 1 to 6, or from 1 to 4, or from 1 to 2; Ra and Rb are eachindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl,heteroalicyclic, hydroxyl, alkoxy, thiol, thioalkoxy, aryloxy, andamine, wherein when m is other than 1, Ra and Rb in each (CRaRb) unitcan be the same or different, and one or both Ra and Rb in one unit canform a 5 to 7-membered alicyclic, heteroalicyclic, aromatic orheteroaromatic ring with one or both Ra and Rb of an adjacent unit; Rcand Rd are each independently hydrogen, alkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxyl, alkoxy, thiol, thioalkoxy,aryloxy, and amine, wherein when n is other than 1, Rc and Rd in each(CRcRd) unit being the same or different, and one or both Rc and Rd inone unit optionally forms a 5 to 7-membered alicyclic, heteroalicyclic,aromatic or heteroaromatic ring with one or both Rc and Rd of anadjacent unit; Rz and Rw are each independently hydrogen, alkyl,cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxyl, alkoxy, thiol,thioalkoxy, aryloxy, and amine, wherein when q is other than 1, Rz andRw in each (CRzRw) unit being the same or different, and one or both Rzand Rw in one unit optionally forms a 5 to 7-membered alicyclic,heteroalicyclic, aromatic or heteroaromatic ring with one or both Rz andRw of an adjacent unit; and R₄₁-R₄₈ and R₃-R₅₆ are each independentlyselected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl,halo, alkoxy, aryloxy, trialkylsilyl, heteroalicyclic, heteroaryl, andamine, provided that: X is other than alkoxy or aryloxy; and/or at leastone of R₄₁ and R₄₂ is a bulky rigid alkyl.
 16. The organometalliccomplex of claim 15, wherein X is halo or amide.
 17. A ligand precursorrepresented by Formula IV:

wherein: m, n and q are each independently an integer of from 1 to 6, orfrom 1 to 4, or from 1 to 2; Ra and Rb are each independently hydrogen,alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxyl, alkoxy,thiol, thioalkoxy, aryloxy, and amine, wherein when m is other than 1,Ra and Rb in each (CRaRb) unit can be the same or different, and one orboth Ra and Rb in one unit can form a 5 to 7-membered alicyclic,heteroalicyclic, aromatic or heteroaromatic ring with one or both Ra andRb of an adjacent unit; Rc and Rd are each independently hydrogen,alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxyl, alkoxy,thiol, thioalkoxy, aryloxy, and amine, wherein when n is other than 1,Rc and Rd in each (CRcRd) unit being the same or different, and one orboth Rc and Rd in one unit optionally forms a 5 to 7-membered alicyclic,heteroalicyclic, aromatic or heteroaromatic ring with one or both Rc andRd of an adjacent unit; Rz and Rw are each independently hydrogen,alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxyl, alkoxy,thiol, thioalkoxy, aryloxy, and amine, wherein when q is other than 1,Rz and Rw in each (CRzRw) unit being the same or different, and one orboth Rz and Rw in one unit optionally forms a 5 to 7-membered alicyclic,heteroalicyclic, aromatic or heteroaromatic ring with one or both Rz andRw of an adjacent unit; and R₄₁-R₄₈ and R₅₃-R₅₆ are each independentlyselected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl,halo, alkoxy, aryloxy, trialkylsilyl, heteroalicyclic, heteroaryl, andamine, provided that at least one of R₄₁ and R₄₂ is a bulky rigid alkyl.